Ageing organisms accumulate senescent cells that are thought to contribute to body dysfunction. Telomere shortening and damage are recognized causes of cellular senescence and ageing. Several human ...conditions associated with normal ageing are precipitated by accelerated telomere dysfunction. Here, we systematize a large body of evidence and propose a coherent perspective to recognize the broad contribution of telomeric dysfunction to human pathologies.
Research on telomeres in the fields of ecology and evolution has been rapidly expanding over the last two decades. This has resulted in the formulation of a multitude of, often name‐given, hypotheses ...related to the associations between telomeres and life‐history traits or fitness‐facilitating processes (and the mechanisms underlying them). However, the differences (or similarities) between the various hypotheses, which can originate from different research fields, are often not obvious. Our aim here is therefore to give an overview of the hypotheses that are of interest in ecology and evolution and to provide two frameworks that help discriminate among them. We group the hypotheses (i) based on their association with different research questions, and (ii) using a hierarchical approach that builds on the assumptions they make, such as about causality of telomere length/shortening and/or the proposed functional consequences of telomere shortening on organism performance. Both our frameworks show that there exist parallel lines of thoughts in different research fields. Moreover, they also clearly illustrate that there are in many cases competing hypotheses within clusters, and that some of these even have contradictory assumptions and/or predictions. We also touch upon two topics in telomere research that would benefit from further conceptualization. This review should help researchers, both those familiar with and those new to the subject, to identify future avenues of research.
Mammalian telomeres have evolved safeguards to prevent their recognition as DNA double‐stranded breaks by suppressing the activation of various DNA sensing and repair proteins. We have shown that the ...telomere‐binding proteins TRF2 and RAP1 cooperate to prevent telomeres from undergoing aberrant homology‐directed recombination by mediating t‐loop protection. Our recent findings also suggest that mammalian telomere‐binding proteins interact with the nuclear envelope to maintain chromosome stability. RAP1 interacts with nuclear lamins through KU70/KU80, and disruption of RAP1 and TRF2 function result in nuclear envelope rupture, promoting telomere‐telomere recombination to form structures termed ultrabright telomeres. In this review, we discuss the importance of the interactions between shelterin components and the nuclear envelope to maintain telomere homeostasis and genome stability.
Our research has shown that the telomere‐binding proteins TRF2 and RAP1 cooperate to prevent the formation of ultrabright telomeres (UT) and suggests that telomere‐binding proteins interact with the nuclear envelope and nuclear lamins to maintain chromosome stability. Both components are critical for the maintenance of telomere homeostasis and genome stability.
Many recent advances have emerged in the telomere and telomerase fields. This Timeline article highlights the key advances that have expanded our views on the mechanistic underpinnings of telomeres ...and telomerase and their roles in ageing and disease. Three decades ago, the classic view was that telomeres protected the natural ends of linear chromosomes and that telomerase was a specific telomere-terminal transferase necessary for the replication of chromosome ends in single-celled organisms. While this concept is still correct, many diverse fields associated with telomeres and telomerase have substantially matured. These areas include the discovery of most of the key molecular components of telomerase, implications for limits to cellular replication, identification and characterization of human genetic disorders that result in premature telomere shortening, the concept that inhibiting telomerase might be a successful therapeutic strategy and roles for telomeres in regulating gene expression. We discuss progress in these areas and conclude with challenges and unanswered questions in the field.
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here ...we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.
Telomeric repeats, coated by the shelterin complex, prevent inappropriate activation of the DNA damage response at the ends of linear chromosomes. Shelterin has evolved distinct solutions to protect ...telomeres from different aspects of the DNA damage response. These solutions include formation of t-loops, which can sequester the chromosome terminus from DNA-end sensors and inhibition of key steps in the DNA damage response. While blocking the DNA damage response at chromosome ends, telomeres make wide use of many of its players to deal with exogenous damage and replication stress. This review focuses on the interplay between the end-protection functions and the response to DNA damage occurring inside the telomeric repeats, as well as on the consequences that telomere damage has on telomere structure and function.
To prevent progressive telomere shortening as a result of conventional DNA replication, new telomeric DNA must be added onto the chromosome end. The de novo DNA synthesis involves elongation of the ...G-rich strand of the telomere by telomerase. In human cells, the CST complex (CTC1-STN1-TEN1) also functions in telomere replication. CST first aids in duplication of the telomeric dsDNA. Then after telomerase has extended the G-rich strand, CST facilitates fill-in synthesis of the complementary C-strand. Here, we analyze telomere structure after disruption of human CTC1 and demonstrate that functional CST is essential for telomere length maintenance due to its role in mediating C-strand fill-in. Removal of CTC1 results in elongation of the 3΄ overhang on the G-rich strand. This leads to accumulation of RPA and telomeric DNA damage signaling. G-overhang length increases with time after CTC1 disruption and at early times net G-strand growth is apparent, indicating telomerase-mediated G-strand extension. In contrast, C-strand length decreases continuously, indicating a deficiency in C-strand fill-in synthesis. The lack of C-strand maintenance leads to gradual shortening of the telomeric dsDNA, similar to that observed in cells lacking telomerase. Thus, telomerase-mediated G-strand extension and CST-mediated C-strand fill-in are equally important for telomere length maintenance.
The number of long-term survivors of patients with various malignancies (>5 years) is increasing mainly owing to advances in cancer therapeutics, but long-term side effects of the cancer treatment in ...this population have emerged as an important health and socio-economical issue. Telomeres and telomerase are known to be essential for regulation of cellular life-span and maintenance of genomic stability, and earlier studies have demonstrated that cancer patients who receive chemotherapy have shorter telomeres in their blood cells, indicating accelerated telomere erosion and a potential contribution of telomere loss to late side-effects. Little is currently known about the effect of chemotherapeutic agents and radiation on telomere dynamics including potential effects on telomere length, structure, function, telomerase activity, and telomere shelterin proteins in normal human cells. In the present study, we had addressed this issue experimentally. The treatment of normal human T lymphocytes and fibroblasts with chemotherapeutic agents doxorubicin (DOX) or etoposide (VP16) led to significant shortening of telomeres, down-regulation of telomerase activity, and diminished expression of telomerase reverse transcriptase (hTERT) and the telomere binding proteins TPP1 and POT1. More importantly, telomere dysfunction was observed in cells treated with DOX or VP16. Furthermore, all the above alterations were similarly found in the cells receiving γ-irradiation. Taken together, both chemotherapy and radiotherapy significantly impair telomere maintenance and function in normal human cells. Conceivably telomere dysfunction causes shortened life-span and genomic instability of normal human cells, and thereby contributes to tissue/organ damage and secondary malignancies in long-term survivors of cancer.
Telomere length is considered a biomarker of biological aging. Shorter telomeres and obesity have both been associated with age-related diseases. To evaluate the association between various indices ...of obesity with leukocyte telomere length (LTL) in childhood, data from 1,396 mother-child pairs of the multi-centre European birth cohort study HELIX were used. Maternal pre-pregnancy body mass index (BMI) and 4 adiposity markers in children at age 8 (6-11) years were assessed: BMI, fat mass, waist circumference, and skinfold thickness. Relative LTL was obtained. Associations of LTL with each adiposity marker were calculated using linear mixed models with a random cohort effect. For each 1 kg/m² increment in maternal pre-pregnancy BMI, the child's LTL was 0.23% shorter (95%CI: 0.01,0.46%). Each unit increase in child BMI z-score was associated with 1.21% (95%CI: 0.30,2.11%) shorter LTL. Inverse associations were observed between waist circumference and LTL (-0.96% per z-score unit; 95%CI: -2.06,0.16%), and skinfold thickness and LTL (-0.10% per z-score unit; 95%CI: -0.23,0.02%). In conclusion, this large multicentric study suggests that higher child adiposity indicators are associated with short telomeres in children, and that associations are stronger for child BMI than for maternal pre-pregnancy BMI.
•Basal cortisol was not correlated with telomere length.•There was a correlation between cortisol reactivity to psychosocial stress and telomere length.•The correlation between cortisol reactivity ...and telomere length varied as a function of some study characteristics.
The objective of the present study is to synthesize the existing empirical literature and perform a meta-analysis of published data on the relationship between cortisol and telomere length. We systematically searched studies that examined the relationship between cortisol and telomere length in humans on electronic databases and screened reference sections of included articles. Fourteen studies were included in the meta-analysis, with effect sizes being extracted for two cortisol measures: basal cortisol levels and cortisol reactivity to acute psychological stress. Results from random effects models showed that basal cortisol levels (13 effect sizes from 12 cross-sectional studies, N = 3675 participants) were not significantly correlated with telomere length (r =−0.05, 95% CI −0.11, 0.02). Further, results stratified by the specimen type for cortisol measurement (i.e., saliva, urine, blood) showed that none of the three basal cortisol level measures were correlated with telomere length. However, we found a statistically significant correlation between salivary cortisol reactivity to acute psychosocial stress (6 cross-sectional studies, N = 958 participants) and telomere length (r = −0.13, 95% CI −0.23, −0.03). Subgroup analyses revealed that correlations between salivary cortisol reactivity and telomere length were more evident in studies conducted among children (vs. adults) and in studies that included female participants only (vs. both genders). However, the small number of available studies limits the conclusions derived from subgroup analyses, and more studies are needed before moderator effects can be properly established. Overall, findings of this study support the existence of a relationship between cortisol reactivity and telomere shortening.
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