scholarly journals TERC Variants Associated with Short Leukocyte Telomeres: Implication of Higher Early Life Leukocyte Telomere Attrition as Assessed by the Blood-and-Muscle Model

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1360
Author(s):  
Simon Toupance ◽  
Maria G. Stathopoulou ◽  
Alexandros M. Petrelis ◽  
Vesna Gorenjak ◽  
Carlos Labat ◽  
...  
Keyword(s):  
Telomere Length ◽  
Early Life ◽  
Telomere Maintenance ◽  
Muscle Model ◽  
Mendelian Randomisation ◽  
Atherosclerotic Cardiovascular Disease ◽  
Nucleotide Polymorphisms ◽  
Telomere Attrition ◽  
Adult Age

Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD). Mendelian randomisation studies, using single nucleotide polymorphisms (SNPs) associated with short LTL, infer a causal role of LTL in ASCVD. Recent results, using the blood-and-muscle model, indicate that higher early life LTL attrition, as estimated by the ratio between LTL and skeletal muscle telomere length (MTL), rather than short LTL at conception, as estimated by MTL, should be responsible of the ASCVD-LTL connection. We combined LTL and MTL measurements and SNPs profiling in 402 individuals to determine if 15 SNPs classically described as associated with short LTL at adult age were rather responsible for higher LTL attrition during early life than for shorter LTL at birth. Two of these SNPs (rs12696304 and rs10936599) were associated with LTL in our cohort (p = 0.027 and p = 0.025, respectively). These SNPs, both located on the TERC gene, were associated with the LTL/MTL ratio (p = 0.007 and p = 0.037, respectively), but not with MTL (p = 0.78 and p = 0.32 respectively). These results suggest that SNPs located on genes coding for telomere maintenance proteins may contribute to a higher LTL attrition during the highly replicative first years of life and have an impact later on the development of ASCVD.

scholarly journals Telomere length and age-dependent telomere attrition: the blood-and-muscle model

2019 ◽  
Vol 97 (4) ◽  
pp. 328-334 ◽  
Author(s):  
Mirna N. Chahine ◽  
Simon Toupance ◽  
Sandy El-Hakim ◽  
Carlos Labat ◽  
Sylvie Gautier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Telomere Length ◽  
Cross Sectional Study ◽  
Muscle Model ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cross Sectional ◽  
Telomere Attrition ◽  
Age Related ◽  
Age Dependent ◽  
Muscle Biopsies

Short telomere length (TL) is associated with atherosclerotic cardiovascular disease (ACVD) and other age-related diseases. It is unclear whether these associations originate from having inherently short TL or a faster TL attrition before or during disease development. We proposed the blood-and-muscle model to assess TL dynamics throughout life course. Our objective was to measure TL in leukocytes (LTL) and in skeletal muscle (MTL), which served as a proxy of TL at birth. The delta (MTL–LTL) represented life-long telomere attrition. Blood draws and skeletal muscle biopsies were performed on 35 Lebanese individuals undergoing surgery. Following DNA extraction, LTL and MTL were measured by Southern blot. In every individual aged between 30 and 85 years, MTL was longer than LTL. With age, MTL and LTL decreased, but the delta (MTL–LTL) increased by 14 bp/year. We validated the blood-and-muscle model that allowed us to identify TL, TL at birth, and lifelong TL attrition in a cross-sectional study. This model can be used in larger cross-sectional studies to evaluate the association of telomere dynamics with age-related diseases onset and progression.

scholarly journals RAD50 and RAD51 Define Two Pathways That Collaborate to Maintain Telomeres in the Absence of Telomerase

Genetics ◽  
1999 ◽  
Vol 152 (1) ◽  
pp. 143-152 ◽  
Author(s):  
Siyuan Le ◽  
J Kent Moore ◽  
James E Haber ◽  
Carol W Greider
Keyword(s):  
Cell Death ◽  
Telomere Length ◽  
Gene Conversion ◽  
De Novo ◽  
Dna Recombination ◽  
Telomere Maintenance ◽  
Triple Mutant ◽  
Yeast Telomerase ◽  
Telomere Lengthening

Abstract Telomere length is maintained by the de novo addition of telomere repeats by telomerase, yet recombination can elongate telomeres in the absence of telomerase. When the yeast telomerase RNA component, TLC1, is deleted, telomeres shorten and most cells die. However, gene conversion mediated by the RAD52 pathway allows telomere lengthening in rare survivor cells. To further investigate the role of recombination in telomere maintenance, we assayed telomere length and the ability to generate survivors in several isogenic DNA recombination mutants, including rad50, rad51, rad52, rad54, rad57, xrs2, and mre11. The rad51, rad52, rad54, and rad57 mutations increased the rate of cell death in the absence of TLC1. In contrast, although the rad50, xrs2, and mre11 strains initially had short telomeres, double mutants with tlc1 did not affect the rate of cell death, and survivors were generated at later times than tlc1 alone. While none of the double mutants of recombination genes and tlc1 (except rad52 tlc1) blocked the ability to generate survivors, a rad50 rad51 tlc1 triple mutant did not allow the generation of survivors. Thus RAD50 and RAD51 define two separate pathways that collaborate to allow cells to survive in the absence of telomerase.

scholarly journals Telomeres, stem cells, and hematology

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 1759-1766 ◽  
Author(s):  
Peter M. Lansdorp
Keyword(s):  
Stem Cells ◽  
Telomere Length ◽  
Cellular Response ◽  
Germ Line ◽  
Critical Role ◽  
Somatic Cells ◽  
Growth Stimulation ◽  
Critical Function ◽  
Telomere Attrition

Telomeres are highly dynamic structures that adjust the cellular response to stress and growth stimulation based on previous cell divisions. This critical function is accomplished by progressive telomere shortening and DNA damage responses activated by chromosome ends without sufficient telomere repeats. Repair of critically short telomeres by telomerase or recombination is limited in most somatic cells, and apoptosis or cellular senescence is triggered when too many uncapped telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germ line that typically express high levels of telomerase. In somatic cells, the telomere length typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal cells in which malignant progression is facilitated by genome instability resulting from uncapped telomeres. The critical role of telomeres in cell proliferation and aging is illustrated in patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Here, the role of telomeres and telomerase in human biology is reviewed from a personal historical perspective.

scholarly journals Nijmegen Breakage Syndrome (NBS) is a Telomeropathy: Analysis of Telomere Length in NBS Homo- and Heterozygotes and Humanized Nbs Mice

2019 ◽  
Author(s):  
Raneem Habib ◽  
Ryong Kim ◽  
Heidemarie Neitzel ◽  
Ilja Demuth ◽  
Krystyna Chrzanowska ◽  
...  
Keyword(s):  
Telomere Length ◽  
Cancer Incidence ◽  
Genetic Instability ◽  
Nijmegen Breakage Syndrome ◽  
Survival Times ◽  
Telomere Shortening ◽  
Cancer Rate ◽  
Telomere Attrition ◽  
After Cancer

AbstractThe autosomal recessive genetic disorder Nijmegen breakage syndrome (NBS) is characterized by a defect in DNA double-strand break repair protein nibrin and chromosome instability associated with a high predisposition to cancer. Here we hypothesized that impaired nibrin/MRE11/RAD50 telomere maintenance complex may also affect telomere length and modulate the cancer phenotype.Telomere length was studied in blood from 38 homozygous and 27 heterozygous individuals, in one homozygous fetus, and in sex NBS lymphoblastoid cell lines (all with the founder mutation c.657_661del5), and in three humanized Nbs mice, using qPCR, TRF and Q-FISH.Telomere lengths were markedly but uniformly reduced to 20-40% of healthy controls. There was no correlation between telomere length and severity of clinical phenotype or age of death. By contrast, individual patients with very short telomeres displayed long survival times after cancer manifestation. Mildly accelerated telomere attrition was found in older NBS heterozygotes. In the NBS-fetus, the spinal cord, brain and heart had the longest telomeres, skin the shortest. Humanized Nbs mice (with much longer telo-meres than those in human beings) did not show accelerated telomere attrition.Our data clearly show that NBS is a secondary telomeropathy with unique features. Te- lomere attrition in NBS may cause genetic instability and contribute to the high cancer incidence in NBS. On the other hand, short telomeres may prevent an even worse pheno-type when a tumor has developed. These data may help to understand the high cancer rate in NBS and also the bifunctional role of telomere shortening in cancerogenesis.Author SummaryDNA damage is harmful because it leads to mutations in genes that initiate or accelerate cancerogenesis. The devastating consequences of DNA damage are manifested in diseases with non-functional repair pathways such as Nijmegen breakage syndrome (NBS). A common feature of these diseases is a high tumor incidence. However, cancer incidence varies and is not clear why it is highest for NBS. In a previous study, we have shown that the underlying nebrin mutation not only leads to defective DNA repair but also to higher degree of oxidative stress that generates further DNA lesions. Nibrin may play also an important role in protecting chromosome ends, the telomeres, from inap-propriate DNA repair. Therefore we examined the telomere length in NBS and show markedly reduced values in affected patients but not in NBC mice (with much milder phenotype and longer telomeres). Telomere attrition contributes to genetic instability and may thus contribute to the high cancer incidence in NBS. Individual patients with very short telomeres, however, displayed long survival times after cancer manifestation. Thus, short telomeres may also prevent an even worse phenotype when a tumor has developed. These data are fundamental to understanding the high cancer rate in NBS and also the bifunctional role of telomere shortening in cancer.

scholarly journals Transcriptional activity of TRF2 is telomere length dependent

2016 ◽  
Author(s):  
Ananda Kishore Mukherjee ◽  
Shalu Sharma ◽  
Parashar Dhapola ◽  
Dhurjhoti Saha ◽  
Tabish Hussain ◽  
...  
Keyword(s):  
Telomere Length ◽  
Genome Stability ◽  
Telomere Maintenance ◽  
Regulatory Control ◽  
Gene Promoters ◽  
Multiple Gene ◽  
Telomere Repeat ◽  
Genome Wide ◽  
Binding Factor

AbstractTRF2 is a telomere repeat binding factor crucial for telomere maintenance and genome stability. An emerging non-conventional role of TRF2 is as a transcriptional regulator through extra-telomeric bindings. Herein we report that increase in telomere length leads to sequestration of TRF2 at the telomeres leading to reduced extra-telomeric TRF2 occupancy genome wide. Decrease in TRF2 occupancy was found on multiple gene promoters in cells with elongated telomeres, including the cell cycle regulator kinase-p21. We found that TRF2 is a transcriptional repressor of p21, and, interestingly, TRF2-mediated regulatory control of p21 is telomere length dependent.

scholarly journals Evaluations of short telomere risk-associated single nucleotide polymorphisms in telomerase reverse transcriptase gene on telomere length maintenance

2019 ◽  
Author(s):  
Jialin Xu ◽  
Matthew A. Trudeau ◽  
Andrew J. Sandford ◽  
Judy M.Y. Wong
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Reverse Transcriptase ◽  
Telomere Length ◽  
Replicative Senescence ◽  
Telomere Maintenance ◽  
Telomerase Reverse Transcriptase ◽  
Nucleotide Polymorphisms ◽  
Primary Cells ◽  
Single Nucleotide ◽  
Telomere Biology

ABSTRACTTelomere biology disorders (TBDs) refer to a spectrum of tissue degenerative disorders caused by genetic mutations in telomere biology genes. Most patients with TBDs suffer from telomere maintenance defects secondary to telomerase deficiency. While the highly penetrant mutations in the telomerase reverse transcriptase (TERT) gene that drive disease onset and progression of TBDs are relatively rare, there exist several single nucleotide polymorphisms (SNPs) in TERT that have been linked to various diseases in the TBD spectrum. In this study, we investigated the biochemical properties of five TERT variants. In an ex vivo cell model, we found that primary human fibroblasts expressing nonsynonymous TERT SNPs had comparable cell growth kinetics to primary cells expressing WT-TERT, while a parallel vector control expressing-cell line entered replicative senescence. At the molecular level, primary cells expressing the minor alleles of two of the five TERT variants (A279T, ΔE441) had replication-dependent loss of telomere length. In an in vitro primer extension assay, these two variants showed reduced telomerase nucleotide addition processivity. Together, our data suggested that selective, common TERT variants could be revealed to harbour telomere maintenance defects, leading to a plausible explanation for their observed associations to telomere biology disorders.

scholarly journals Telomeres and Cancer

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1405
Author(s):  
Hueng-Chuen Fan ◽  
Fung-Wei Chang ◽  
Jeng-Dau Tsai ◽  
Kao-Min Lin ◽  
Chuan-Mu Chen ◽  
...  
Keyword(s):  
Telomere Length ◽  
Molecular Mechanisms ◽  
Telomere Maintenance ◽  
Cancer Development ◽  
Telomere Elongation ◽  
Metabolism Pathway ◽  
Length Regulation ◽  
Telomere Length Regulation ◽  
Genome Protection

Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation. This review describes the telomere functions, the role of functional modulators, the implications in cancer development, and the future therapeutic opportunities.

scholarly journals Telomeres and Longevity: A Cause or an Effect?

2019 ◽  
Vol 20 (13) ◽  
pp. 3233 ◽  
Author(s):  
Huda Adwan Shekhidem ◽  
Lital Sharvit ◽  
Eva Leman ◽  
Irena Manov ◽  
Asael Roichman ◽  
...  
Keyword(s):  
Telomere Length ◽  
Ongoing Debate ◽  
Telomere Attrition ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Extreme Longevity ◽  
Linear Chromosomes ◽  
Biological State

Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a “biological thermometer” that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.

scholarly journals Mother–offspring and nest-mate resemblance but no heritability in early-life telomere length in white-throated dippers

2015 ◽  
Vol 282 (1807) ◽  
pp. 20142924 ◽  
Author(s):  
Philipp J. J. Becker ◽  
Sophie Reichert ◽  
Sandrine Zahn ◽  
Johann Hegelbach ◽  
Sylvie Massemin ◽  
...  
Keyword(s):  
Telomere Length ◽  
Early Life ◽  
Evolutionary Dynamics ◽  
Protein Complexes ◽  
Additive Genetic Variance ◽  
Pedigree Data ◽  
Genes And Environment ◽  
Cinclus Cinclus ◽  
Maternal Imprinting

Telomeres are protective DNA–protein complexes located at the ends of eukaryotic chromosomes, whose length has been shown to predict life-history parameters in various species. Although this suggests that telomere length is subject to natural selection, its evolutionary dynamics crucially depends on its heritability. Using pedigree data for a population of white-throated dippers ( Cinclus cinclus ), we test whether and how variation in early-life relative telomere length (RTL, measured as the number of telomeric repeats relative to a control gene using qPCR) is transmitted across generations. We disentangle the relative effects of genes and environment and test for sex-specific patterns of inheritance. There was strong and significant resemblance among offspring sharing the same nest and offspring of the same cohort. Furthermore, although offspring resemble their mother, and there is some indication for an effect of inbreeding, additive genetic variance and heritability are close to zero. We find no evidence for a role of either maternal imprinting or Z-linked inheritance in generating these patterns, suggesting they are due to non-genetic maternal and common environment effects instead. We conclude that in this wild bird population, environmental factors are the main drivers of variation in early-life RTL, which will severely bias estimates of heritability when not modelled explicitly.

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