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15 pages, 1578 KiB

Open AccessArticle

Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma

by Nazmul Huda, Yan Xu, Alison M. Bates, Deborah A. Rankin, Nagarajan Kannan and David Gilley

Cells 2019, 8(5), 414; https://doi.org/10.3390/cells8050414 - 4 May 2019

Cited by 5 | Viewed by 3311

Abstract

Telomere dysfunction has been strongly implicated in the initiation of genomic instability and is suspected to be an early event in the carcinogenesis of human solid tumors. Recent findings have established the presence of telomere fusions in human breast and prostate malignancies; however, [...] Read more.

Telomere dysfunction has been strongly implicated in the initiation of genomic instability and is suspected to be an early event in the carcinogenesis of human solid tumors. Recent findings have established the presence of telomere fusions in human breast and prostate malignancies; however, the onset of this genomic instability mechanism during progression of other solid cancers is not well understood. Herein, we explored telomere dynamics in patient-derived epithelial ovarian cancers (OC), a malignancy characterized by multiple distinct subtypes, extensive molecular heterogeneity, and widespread genomic instability. We discovered a high frequency of telomere fusions in ovarian tumor tissues; however, limited telomere fusions were detected in normal adjacent tissues or benign ovarian samples. In addition, we found relatively high levels of both telomerase activity and hTERT expression, along with anaphase bridges in tumor tissues, which were notably absent in adjacent normal ovarian tissues and benign lesions. These results suggest that telomere dysfunction may occur early in ovarian carcinogenesis and, importantly, that it may play a critical role in the initiation and progression of the disease. Recognizing telomere dysfunction as a pervasive feature of this heterogeneous malignancy may facilitate the future development of novel diagnostic tools and improved methods of disease monitoring and treatment. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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12 pages, 742 KiB

Open AccessArticle

Telomere Length and Risk of Major Adverse Cardiac Events and Cancer in Obstructive Sleep Apnea Patients

by Katarzyna Polonis, Sreeja Sompalli, Christiane Becari, Jiang Xie, Naima Covassin, Phillip J Schulte, Brooke R Druliner, Ruth A Johnson, Krzysztof Narkiewicz, Lisa A Boardman, Prachi Singh and Virend K Somers

Cells 2019, 8(5), 381; https://doi.org/10.3390/cells8050381 - 26 Apr 2019

Cited by 10 | Viewed by 3641

Abstract

Telomere length (TL) is associated with cardiovascular disease (CVD) and cancer. Obstructive sleep apnea (OSA) is also linked to higher risk of CVD and cancer, and to TL. We investigated the association between TL and risk of major adverse cardiac events (MACE) and [...] Read more.

Telomere length (TL) is associated with cardiovascular disease (CVD) and cancer. Obstructive sleep apnea (OSA) is also linked to higher risk of CVD and cancer, and to TL. We investigated the association between TL and risk of major adverse cardiac events (MACE) and cancer in OSA patients. We studied 210 individuals undergoing sleep-related studies between 2000 and 2007. Baseline characteristics and follow-up data (available in 164 subjects) were obtained from clinic records. Incidence rates were calculated for the entire group and by OSA status. Hazard ratios were calculated to estimate effects of OSA and TL on risk of MACE and cancer. In total, 32 individuals (20%) developed MACE and/or cancer during 12.7-year follow-up. The OSA group had a higher likelihood of cancer (16.0 vs. 4.9 events per 1000 person-years, P = 0.044) but no clear evidence of an elevated incidence of MACE (10.8 vs. 4.8 events per 1000 person-years, P = 0.293) compared to the non-OSA group. There was no association between TL and MACE- (HR = 1.01, 95% CI 0.78–1.28), or cancer-risk (HR = 1.18, 95% CI 0.96–1.43). Our study warrants further investigation of any modulating effect of OSA on TL and the risk of MACE and cancer. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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15 pages, 3667 KiB

Open AccessArticle

3D Telomere Structure Analysis to Detect Genomic Instability and Cytogenetic Evolution in Myelodysplastic Syndromes

by Aline Rangel-Pozzo, Daiane Corrêa de Souza, Ana Teresa Schmid-Braz, Ana Paula de Azambuja, Thais Ferraz-Aguiar, Tamara Borgonovo and Sabine Mai

Cells 2019, 8(4), 304; https://doi.org/10.3390/cells8040304 - 2 Apr 2019

Cited by 7 | Viewed by 3294

Abstract

The disease course of myelodysplastic syndromes (MDS) features chromosome instability and clonal evolution, leading to the sequential acquisition of novel cytogenetic aberrations and the accumulation of these abnormalities in the bone marrow. Although clonal cytogenetic abnormalities can be detected by conventional cytogenetics in [...] Read more.

The disease course of myelodysplastic syndromes (MDS) features chromosome instability and clonal evolution, leading to the sequential acquisition of novel cytogenetic aberrations and the accumulation of these abnormalities in the bone marrow. Although clonal cytogenetic abnormalities can be detected by conventional cytogenetics in 50% of patients with MDS, such distinguishing patterns are lacking in the other 50%. Despite the increase in the prognostic value of some biomarkers, none of them is specific and able to discriminate between stable and unstable patients that subsequently progress to acute myeloid leukemia. This pilot study aimed to investigate the potential use of the 3D telomere profiling to detect genomic instability in MDS patients with or without clonal cytogenetic evolution. The comparison between different time points in patients with cytogenetic changes showed that in the CD34+ MDS cells, there was a significant decrease in the total number of telomeric signals, the average intensity of signals and the total intensity of telomeres. By contrast, the number of aggregates increased during cytogenetic evolution (p < 0.001). This pattern was observed only for MDS patients with cytogenetic evolution but was absent in patients without cytogenetic changes. In conclusion, we demonstrated that the 3D nuclear telomere organization was significantly altered during the MDS disease course, and may have contributed to cytogenetic clonal evolution. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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17 pages, 2535 KiB

Open AccessArticle

Direct Single-Cell Analysis of Human Polar Bodies and Cleavage-Stage Embryos Reveals No Evidence of the Telomere Theory of Reproductive Ageing in Relation to Aneuploidy Generation

by Kara Turner, Colleen Lynch, Hannah Rouse, Vimal Vasu and Darren K. Griffin

Cells 2019, 8(2), 163; https://doi.org/10.3390/cells8020163 - 16 Feb 2019

Cited by 8 | Viewed by 6554

Abstract

Reproductive ageing in women, particularly after the age of 35, is associated with an exponential increase in the proportion of chromosomally abnormal oocytes produced. Several hypotheses have attempted to explain this observation, including the ‘limited oocyte pool’ hypothesis and the ‘two-hit’ hypothesis, the [...] Read more.

Reproductive ageing in women, particularly after the age of 35, is associated with an exponential increase in the proportion of chromosomally abnormal oocytes produced. Several hypotheses have attempted to explain this observation, including the ‘limited oocyte pool’ hypothesis and the ‘two-hit’ hypothesis, the latter explaining that a depletion in oocyte quality with age results from the multiple opportune stages for errors to occur in meiosis. Recently however, the telomere theory of reproductive ageing in women has been proposed. This suggests that shortened telomeres in oocytes of women of advanced maternal age render oocytes unable to support fertilization and embryogenesis. Despite a credible rationale for the telomere theory of reproductive ageing in women, very few studies have assessed telomere length directly in human oocytes or preimplantation embryos. Therefore, we directly assessed relative telomere length in first polar bodies and blastomeres from cleavage stage (day 3) embryos. In both cell types we tested the hypothesis that (1) older women have shorter telomeres and (2) chromosomally abnormal (aneuploid) gametes/embryos have shorter telomeres. In all cases, we found no evidence of altered telomere length associated with age-related aneuploidy. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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10 pages, 701 KiB

Open AccessArticle

No Causal Effect of Telomere Length on Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study

by Weijie Cao, Xingang Li, Xiaoyu Zhang, Jie Zhang, Qi Sun, Xizhu Xu, Ming Sun, Qiuyue Tian, Qihuan Li, Hao Wang, Jiaonan Liu, Xiaoni Meng, Lijuan Wu, Manshu Song, Haifeng Hou, Youxin Wang and Wei Wang

Cells 2019, 8(2), 159; https://doi.org/10.3390/cells8020159 - 14 Feb 2019

Cited by 26 | Viewed by 4764

Abstract

Background: Epidemiological studies observing inconsistent associations of telomere length (TL) with ischemic stroke (IS) are susceptible to bias according to reverse causation and residual confounding. We aimed to assess the causal association between TL, IS, and the subtypes of IS, including large artery [...] Read more.

Background: Epidemiological studies observing inconsistent associations of telomere length (TL) with ischemic stroke (IS) are susceptible to bias according to reverse causation and residual confounding. We aimed to assess the causal association between TL, IS, and the subtypes of IS, including large artery stroke (LAS), small vessel stroke (SVS), and cardioembolic stroke (CES) by performing a series of two-sample Mendelian randomization (MR) approaches. Methods: Seven single nucleotide polymorphisms (SNPs) were involved as candidate instrumental variables (IVs), summarized from a genome-wide meta-analysis including 37,684 participants of European descent. We analyzed the largest ever genome-wide association studies of stroke in Europe from the MEGASTROKE collaboration with 40,585 stroke cases and 406,111 controls. The weighted median (WM), the penalized weighted median (PWM), the inverse variance weighted (IVW), the penalized inverse variance weighted (PIVW), the robust inverse variance weighted (RIVW), and the Mendelian randomization-Egger (MR-Egger) methods were conducted for the MR analysis to estimate a causal effect and detect the directional pleiotropy. Results: No significant association between genetically determined TL with overall IS, LAS, or CES were found (all p > 0.05). SVS was associated with TL by the RIVW method (odds ratio (OR) = 0.72, 95% confidence interval (CI): 0.54–0.97, p = 0.028), after excluding rs9420907, rs10936599, and rs2736100. Conclusions: By a series of causal inference approaches using SNPs as IVs, no strong evidence to support the causal effect of shorter TL on IS and its subtypes were found. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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13 pages, 268 KiB

Open AccessArticle

Leukocyte Telomere Length and Chronic Conditions in Older Women of Northeast Brazil: A Cross-Sectional Study

by Bruna Silva Oliveira, Catherine M. Pirkle, Maria Victoria Zunzunegui, Silvia Regina Batistuzzo de Medeiros, Ronaldo Luis Thomasini and Ricardo Oliveira Guerra

Cells 2018, 7(11), 193; https://doi.org/10.3390/cells7110193 - 2 Nov 2018

Cited by 4 | Viewed by 3655

Abstract

This study assessed whether telomere length is related to chronic conditions, cardiovascular risk factors, and inflammation in women aged 65 to 74 from Northeast Brazil. Participants were selected from two sources, a representative sample of the International Mobility in Aging Study (n [...] Read more.

This study assessed whether telomere length is related to chronic conditions, cardiovascular risk factors, and inflammation in women aged 65 to 74 from Northeast Brazil. Participants were selected from two sources, a representative sample of the International Mobility in Aging Study (n = 57) and a convenience sample (n = 49) recruited at senior centers. Leukocyte telomere length was measured by quantitative polymerase chain reaction from blood samples in 83 women. Natural log-transformed telomere/single copy gene ratio was used as the dependent variable in the analysis. Blood analyses included inflammatory markers (high-sensitivity C-reactive protein and interleukin-6), total, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides, glucose and glycosylated hemoglobin. Self-rated health, chronic conditions, cardiovascular risk factors and inflammatory markers were not associated with telomere length. No significant independent association was found between telomere length and anthropometric measures or blood markers, even after adjusting for age, education and adverse childhood events among these older women in Northeast Brazil. Our results did not confirm the hypothesis that chronic conditions, cardiovascular risk factors or inflammation are associated with shorter telomere length in these women who have exceptional survival relative to the life expectancy of their birth cohort. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

10 pages, 1329 KiB

Open AccessArticle

Telomere Length Calibration from qPCR Measurement: Limitations of Current Method

by Youjin Wang, Sharon A. Savage, Rotana Alsaggaf, Geraldine Aubert, Casey L. Dagnall, Stephen R. Spellman, Stephanie J. Lee, Belynda Hicks, Kristine Jones, Hormuzd A. Katki and Shahinaz M. Gadalla

Cells 2018, 7(11), 183; https://doi.org/10.3390/cells7110183 - 24 Oct 2018

Cited by 23 | Viewed by 5317

Abstract

Telomere length (TL) comparisons from different methods are challenging due to differences in laboratory techniques and data configuration. This study aimed to assess the validity of converting the quantitative polymerase chain reaction (qPCR) telomere/single copy gene (T/S) ratio to TL in kilobases (kb). [...] Read more.

Telomere length (TL) comparisons from different methods are challenging due to differences in laboratory techniques and data configuration. This study aimed to assess the validity of converting the quantitative polymerase chain reaction (qPCR) telomere/single copy gene (T/S) ratio to TL in kilobases (kb). We developed a linear regression equation to predict TL from qPCR T/S using flow cytometry with fluorescence in situ hybridization (flow FISH) TL data from 181 healthy donors (age range = 19–53) from the National Marrow Donor Program (NMDP) biorepository. TL measurements by qPCR and flow FISH were modestly correlated (R² = 0.56, p < 0.0001). In Bland-Altman analyses, individuals with the shortest (≤10th percentile) or longest (≥90th) flow FISH TL had an over- or under-estimated qPCR TL (bias = 0.89 and −0.77 kb, respectively). Comparisons of calculated TL from the NMDP samples and 1810 age- and sex-matched individuals from the National Health and Nutrition Examination Survey showed significant differences (median = 7.1 versus 5.8 kb, respectively, p < 0.0001). Differences in annual TL attrition were also noted (31 versus 13 bp/year, respectively, p = 0.02). Our results demonstrate that TL calculated in kb from qPCR T/S may yield biased estimates for individuals with the shortest or longest TL, those often of high clinical interest. We also showed that calculated TL in kb from qPCR data are not comparable across populations and therefore are not necessarily useful. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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19 pages, 8046 KiB

Open AccessArticle

The Effect of Ethanol on Telomere Dynamics and Regulation in Human Cells

by Tomer Harpaz, Heba Abumock, Einat Beery, Yonatan Edel, Meir Lahav, Uri Rozovski and Orit Uziel

Cells 2018, 7(10), 169; https://doi.org/10.3390/cells7100169 - 15 Oct 2018

Cited by 24 | Viewed by 4688

Abstract

Telomeres (TLs) protect chromosome ends from chromosomal fusion and degradation, thus conferring genomic stability, and play crucial roles in cellular aging and disease. Recent studies have found a correlation between environmental, physiological and even mental stresses on TL dynamics in humans. However, the [...] Read more.

Telomeres (TLs) protect chromosome ends from chromosomal fusion and degradation, thus conferring genomic stability, and play crucial roles in cellular aging and disease. Recent studies have found a correlation between environmental, physiological and even mental stresses on TL dynamics in humans. However, the causal relationship between stress and TL length and the molecular mechanisms underlying that relationship are far from being understood. This study describes the effect of moderate concentrations of ethanol, equivalent to social drinking, on human TL dynamics and partially elucidates the mechanism mediating this effect. The exposure of Immortalized human foreskin fibroblast, primary human foreskin fibroblast and human hepatocellular carcinoma cells to 25 mM ethanol for one week moderately shortened telomeres in all cells. Similar TL shortening was obtained following cells’ exposure to 25 µM acetaldehyde (AcH) and to a much lower extent after exposure to 4-methylpyrazolean, an inhibitor of alcoholdehydrogenase, suggesting that AcH plays a key role in ethanol-dependent telomere shortening. Telomerase activity was not involved in this effect. TRF2 and several TRF2 binding proteins increased their binding to TLs after ethanol treatment, implying their involvement in this effect. The methylation status of several sub-telomeric regions increased in response to EtOH exposure. Gene expression profiling showed distinct patterns in cells treated with EtOH and in cells recovered from EtOH. In addition to cellular ageing, the described telomere shortening may contribute to the carcinogenic potential of acute alcohol consumption; both are associated with the shortening of TLs and provide new insights regarding the moderate consumption of alcohol referred to as “social drinking.” Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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Review

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17 pages, 270 KiB

Open AccessReview

Telomere Gene Therapy: Polarizing Therapeutic Goals for Treatment of Various Diseases

by JinWoo Hong and Chae-Ok Yun

Cells 2019, 8(5), 392; https://doi.org/10.3390/cells8050392 - 28 Apr 2019

Cited by 19 | Viewed by 6321

Abstract

Modulation of telomerase maintenance by gene therapy must meet two polarizing requirements to achieve different therapeutic outcomes: Anti-aging/regenerative applications require upregulation, while anticancer applications necessitate suppression of various genes integral to telomere maintenance (e.g., telomerase, telomerase RNA components, and shelterin complex). Patients suffering [...] Read more.

Modulation of telomerase maintenance by gene therapy must meet two polarizing requirements to achieve different therapeutic outcomes: Anti-aging/regenerative applications require upregulation, while anticancer applications necessitate suppression of various genes integral to telomere maintenance (e.g., telomerase, telomerase RNA components, and shelterin complex). Patients suffering from aging-associated illnesses often exhibit telomere attrition, which promotes chromosomal instability and cellular senescence, thus requiring the transfer of telomere maintenance-related genes to improve patient outcomes. However, reactivation and overexpression of telomerase are observed in 85% of cancer patients; this process is integral to cancer immortality. Thus, telomere-associated genes in the scope of cancer gene therapy must be inactivated or inhibited to induce anticancer effects. These contradicting requirements for achieving different therapeutic outcomes mean that any vector-mediated upregulation of telomere-associated genes must be accompanied by rigorous evaluation of potential oncogenesis. Thus, this review aims to discuss how telomere-associated genes are being targeted or utilized in various gene therapy applications and provides some insight into currently available safety hazard assessments. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

18 pages, 719 KiB

Open AccessReview

The Emerging Roles of TERRA in Telomere Maintenance and Genome Stability

by Nicole Bettin, Claudio Oss Pegorar and Emilio Cusanelli

Cells 2019, 8(3), 246; https://doi.org/10.3390/cells8030246 - 15 Mar 2019

Cited by 114 | Viewed by 13238

Abstract

The finding that transcription occurs at chromosome ends has opened new fields of study on the roles of telomeric transcripts in chromosome end maintenance and genome stability. Indeed, the ends of chromosomes are required to be protected from activation of DNA damage response [...] Read more.

The finding that transcription occurs at chromosome ends has opened new fields of study on the roles of telomeric transcripts in chromosome end maintenance and genome stability. Indeed, the ends of chromosomes are required to be protected from activation of DNA damage response and DNA repair pathways. Chromosome end protection is achieved by the activity of specific proteins that associate with chromosome ends, forming telomeres. Telomeres need to be constantly maintained as they are in a heterochromatic state and fold into specific structures (T-loops), which may hamper DNA replication. In addition, in the absence of maintenance mechanisms, chromosome ends shorten at every cell division due to limitations in the DNA replication machinery, which is unable to fully replicate the extremities of chromosomes. Altered telomere structure or critically short chromosome ends generate dysfunctional telomeres, ultimately leading to replicative senescence or chromosome instability. Telomere biology is thus implicated in multiple human diseases, including cancer. Emerging evidence indicates that a class of long noncoding RNAs transcribed at telomeres, known as TERRA for “TElomeric Repeat-containing RNA,” actively participates in the mechanisms regulating telomere maintenance and chromosome end protection. However, the molecular details of TERRA activities remain to be elucidated. In this review, we discuss recent findings on the emerging roles of TERRA in telomere maintenance and genome stability and their implications in human diseases. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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13 pages, 1041 KiB

Open AccessReview

Histone Modifications and the Maintenance of Telomere Integrity

by Meagan Jezek and Erin M. Green

Cells 2019, 8(2), 199; https://doi.org/10.3390/cells8020199 - 25 Feb 2019

Cited by 28 | Viewed by 10787

Abstract

Telomeres, the nucleoprotein structures at the ends of eukaryotic chromosomes, play an integral role in protecting linear DNA from degradation. Dysregulation of telomeres can result in genomic instability and has been implicated in increased rates of cellular senescence and many diseases, including cancer. [...] Read more.

Telomeres, the nucleoprotein structures at the ends of eukaryotic chromosomes, play an integral role in protecting linear DNA from degradation. Dysregulation of telomeres can result in genomic instability and has been implicated in increased rates of cellular senescence and many diseases, including cancer. The integrity of telomeres is maintained by a coordinated network of proteins and RNAs, such as the telomerase holoenzyme and protective proteins that prevent the recognition of the telomere ends as a DNA double-strand breaks. The structure of chromatin at telomeres and within adjacent subtelomeres has been implicated in telomere maintenance pathways in model systems and humans. Specific post-translational modifications of histones, including methylation, acetylation, and ubiquitination, have been shown to be necessary for maintaining a chromatin environment that promotes telomere integrity. Here we review the current knowledge regarding the role of histone modifications in maintaining telomeric and subtelomeric chromatin, discuss the implications of histone modification marks as they relate to human disease, and highlight key areas for future research. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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13 pages, 1328 KiB

Open AccessReview

Targeting Telomeres and Telomerase: Studies in Aging and Disease Utilizing CRISPR/Cas9 Technology

by Andrew C. Brane and Trygve O. Tollefsbol

Cells 2019, 8(2), 186; https://doi.org/10.3390/cells8020186 - 21 Feb 2019

Cited by 19 | Viewed by 9424

Abstract

Telomeres and telomerase provide a unique and important avenue of study in improving both life expectancy and quality of life due to their close association with aging and disease. While major advances in our understanding of these two biological mediators have characterized the [...] Read more.

Telomeres and telomerase provide a unique and important avenue of study in improving both life expectancy and quality of life due to their close association with aging and disease. While major advances in our understanding of these two biological mediators have characterized the last two decades, previous studies have been limited by the inability to affect change in real time within living cells. The last three years, however, have witnessed a huge step forward to overcome this limitation. The advent of the clustered regularly interspaced short palindromic repeats/CRISPR-associated (CRISPR/Cas) system has led to a wide array of targeted genetic studies that are already being employed to modify telomeres and telomerase, as well as the genes that affect them. In this review, we analyze studies utilizing the technology to target and modify telomeres, telomerase, and their closely associated genes. We also discuss how these studies can provide insight into the biology and mechanisms that underlie aging, cancer, and other diseases. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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10 pages, 641 KiB

Open AccessReview

Roles of Telomere Biology in Cell Senescence, Replicative and Chronological Ageing

by Jun Liu, Lihui Wang, Zhiguo Wang and Jun-Ping Liu

Cells 2019, 8(1), 54; https://doi.org/10.3390/cells8010054 - 15 Jan 2019

Cited by 112 | Viewed by 12564

Abstract

Telomeres with G-rich repetitive DNA and particular proteins as special heterochromatin structures at the termini of eukaryotic chromosomes are tightly maintained to safeguard genetic integrity and functionality. Telomerase as a specialized reverse transcriptase uses its intrinsic RNA template to lengthen telomeric G-rich strand [...] Read more.

Telomeres with G-rich repetitive DNA and particular proteins as special heterochromatin structures at the termini of eukaryotic chromosomes are tightly maintained to safeguard genetic integrity and functionality. Telomerase as a specialized reverse transcriptase uses its intrinsic RNA template to lengthen telomeric G-rich strand in yeast and human cells. Cells sense telomere length shortening and respond with cell cycle arrest at a certain size of telomeres referring to the “Hayflick limit.” In addition to regulating the cell replicative senescence, telomere biology plays a fundamental role in regulating the chronological post-mitotic cell ageing. In this review, we summarize the current understandings of telomere regulation of cell replicative and chronological ageing in the pioneer model system Saccharomyces cerevisiae and provide an overview on telomere regulation of animal lifespans. We focus on the mechanisms of survivals by telomere elongation, DNA damage response and environmental factors in the absence of telomerase maintenance of telomeres in the yeast and mammals. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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15 pages, 433 KiB

Open AccessReview

Mood Disorders, Accelerated Aging, and Inflammation: Is the Link Hidden in Telomeres?

by Alessio Squassina, Claudia Pisanu and Roberta Vanni

Cells 2019, 8(1), 52; https://doi.org/10.3390/cells8010052 - 15 Jan 2019

Cited by 42 | Viewed by 8052

Abstract

Mood disorders are associated with an increased risk of aging-related diseases, which greatly contribute to the excess morbidity and mortality observed in affected individuals. Clinical and molecular findings also suggest that mood disorders might be characterized by a permanent state of low-grade inflammation. [...] Read more.

Mood disorders are associated with an increased risk of aging-related diseases, which greatly contribute to the excess morbidity and mortality observed in affected individuals. Clinical and molecular findings also suggest that mood disorders might be characterized by a permanent state of low-grade inflammation. At the cellular level, aging translates into telomeres shortening. Intriguingly, inflammation and telomere shortening show a bidirectional association: a pro-inflammatory state seems to contribute to aging and telomere dysfunction, and telomere attrition is able to induce low-grade inflammation. Several independent studies have reported shorter telomere length and increased levels of circulating inflammatory cytokines in mood disorders, suggesting a complex interplay between altered inflammatory–immune responses and telomere dynamics in the etiopathogenesis of these disorders. In this review, we critically discuss studies investigating the role of telomere attrition and inflammation in the pathogenesis and course of mood disorders, and in pharmacological treatments with psychotropic medications. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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19 pages, 1349 KiB

Open AccessReview

Bring It to an End: Does Telomeres Size Matter?

by Camille Laberthonnière, Frédérique Magdinier and Jérôme D. Robin

Cells 2019, 8(1), 30; https://doi.org/10.3390/cells8010030 - 8 Jan 2019

Cited by 18 | Viewed by 7408

Abstract

Telomeres are unique nucleoprotein structures. Found at the edge of each chromosome, their main purpose is to mask DNA ends from the DNA-repair machinery by formation of protective loops. Through life and cell divisions, telomeres shorten and bring cells closer to either cell [...] Read more.

Telomeres are unique nucleoprotein structures. Found at the edge of each chromosome, their main purpose is to mask DNA ends from the DNA-repair machinery by formation of protective loops. Through life and cell divisions, telomeres shorten and bring cells closer to either cell proliferation crisis or senescence. Beyond this mitotic clock role attributed to the need for telomere to be maintained over a critical length, the very tip of our DNA has been shown to impact transcription by position effect. TPE and a long-reach counterpart, TPE-OLD, are mechanisms recently described in human biology. Still in infancy, the mechanism of action of these processes and their respective genome wide impact remain to be resolved. In this review, we will discuss recent findings on telomere dynamics, TPE, TPE-OLD, and lessons learnt from model organisms. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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Other

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10 pages, 1452 KiB

Open AccessPerspective

Assessing the Epigenetic Status of Human Telomeres

by María I. Vaquero-Sedas and Miguel A. Vega-Palas

Cells 2019, 8(9), 1050; https://doi.org/10.3390/cells8091050 - 7 Sep 2019

Cited by 11 | Viewed by 3726

Abstract

The epigenetic modifications of human telomeres play a relevant role in telomere functions and cell proliferation. Therefore, their study is becoming an issue of major interest. These epigenetic modifications are usually analyzed by microscopy or by chromatin immunoprecipitation (ChIP). However, these analyses could [...] Read more.

The epigenetic modifications of human telomeres play a relevant role in telomere functions and cell proliferation. Therefore, their study is becoming an issue of major interest. These epigenetic modifications are usually analyzed by microscopy or by chromatin immunoprecipitation (ChIP). However, these analyses could be challenged by subtelomeres and/or interstitial telomeric sequences (ITSs). Whereas telomeres and subtelomeres cannot be differentiated by microscopy techniques, telomeres and ITSs might not be differentiated in ChIP analyses. In addition, ChIP analyses of telomeres should be properly controlled. Hence, studies focusing on the epigenetic features of human telomeres have to be carefully designed and interpreted. Here, we present a comprehensive discussion on how subtelomeres and ITSs might influence studies of human telomere epigenetics. We specially focus on the influence of ITSs and some experimental aspects of the ChIP technique on ChIP analyses. In addition, we propose a specific pipeline to accurately perform these studies. This pipeline is very simple and can be applied to a wide variety of cells, including cancer cells. Since the epigenetic status of telomeres could influence cancer cells proliferation, this pipeline might help design precise epigenetic treatments for specific cancer types. Full article

(This article belongs to the Special Issue The Role of Telomere Biology in Aging and Human Disease)

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