Highlights • Telomere shortening predicts numerous diseases and may be a biomarker of aging. • Past research suggests stress may be related to telomere shortening. • We find a very small pooled ...correlation between increased stress and short telomeres. • Future work should address possible publication bias and improve stress measurement.
Telomeres are the protective end-complexes at the termini of eukaryotic chromosomes. Telomere attrition can lead to potentially maladaptive cellular changes, block cell division, and interfere with ...tissue replenishment. Recent advances in the understanding of human disease processes have clarified the roles of telomere biology, especially in diseases of human aging and in some aging-related processes. Greater overall telomere attrition predicts mortality and aging-related diseases in inherited telomere syndrome patients, and also in general human cohorts. However, genetically caused variations in telomere maintenance either raise or lower risks and progression of cancers, in a highly cancer type–specific fashion. Telomere maintenance is determined by genetic factors and is also cumulatively shaped by nongenetic influences throughout human life; both can interact. These and other recent findings highlight both causal and potentiating roles for telomere attrition in human diseases.
•Periampullary carcinomas (PAC) are uncommon and heterogeneous groups of malignancies that develop from various anatomic locations near the ampulla of Vater.•The characteristics of the TERT gene and ...telomere in PAC are not well studied.•We identified a hypermethylated region in the TERT promoter consisting of four CpGs and a polymorphism in 45% of the cases at rs2853669 (T > C).•We also detected shorter in PAC tissues compared to adjacent normal tissues.•These results could be used further to investigate molecular pathology and develop theranostics for PAC.
Genetic and epigenetic alterations of the telomere maintenance machinery like telomere length and telomerase reverse transcriptase (encoded by TERT gene) are reported in several human malignancies. However, there is limited knowledge on the status of the telomere machinery in periampullary carcinomas (PAC) which are rare and heterogeneous groups of cancers arising from different anatomic sites around the ampulla of Vater. In the current study, we investigated the relative telomere length (RTL) and the most frequent genetic and epigenetic alterations in the TERT promoter in PAC and compared it with tumor-adjacent nonpathological duodenum (NDu). We found shorter RTLs (1.27 vs 1.33, P = 0.01) and lower TERT protein expression (p = 0.04) in PAC tissues as compared to the NDu. Although we did not find any mutation at two reactivating hotspot mutation sites of the TERT promoter, we detected polymorphism in 45% (9/20) of the cases at rs2853669 (T > C). Also, we found a hypermethylated region in the TERT promoter of PACs consisting of four CpGs (cg10896616 with Δβ 7%; cg02545192 with Δβ 9%; cg03323598 with Δβ 19%; and cg07285213 with Δβ 15%). In conclusion, we identified shorter telomeres with DNA hypermethylation in the TERT promoter region and lower TERT protein expression in PAC tissues. These results could be used further to investigate molecular pathology and develop theranostics for PAC.
POT1 and TPP1 are part of the shelterin complex and are essential for telomere length regulation and maintenance. Naturally occurring mutations of the telomeric POT1-TPP1 complex are implicated in ...familial glioma, melanoma and chronic lymphocytic leukaemia. Here we report the atomic structure of the interacting portion of the human telomeric POT1-TPP1 complex and suggest how several of these mutations contribute to malignant cancer. The POT1 C-terminus (POT1C) forms a bilobal structure consisting of an OB-fold and a holiday junction resolvase domain. TPP1 consists of several loops and helices involved in extensive interactions with POT1C. Biochemical data shows that several of the cancer-associated mutations, partially disrupt the POT1-TPP1 complex, which affects its ability to bind telomeric DNA efficiently. A defective POT1-TPP1 complex leads to longer and fragile telomeres, which in turn promotes genomic instability and cancer.
The cellular senescence definition comes to the fact of cells irreversible proliferation disability. Besides the cell cycle arrest, senescent cells go through some morphological, biochemical, and ...functional changes which are the signs of cellular senescence. The senescent cells (including replicative senescence and stress-induced premature senescence) of all the tissues look alike. They are metabolically active and possess the set of characteristics in vitro and in vivo, which are known as biomarkers of aging and cellular senescence. Among biomarkers of cellular senescence telomere shortening is a rather elegant frequently used biomarker. Validity of telomere shortening as a marker for cellular senescence is based on theoretical and experimental data.
The majority of high-risk neuroblastomas can be divided into three distinct molecular subgroups defined by the presence of MYCN amplification, upstream TERT rearrangements or alternative lengthening ...of telomeres (ALT). The common defining feature of all three subgroups is altered telomere maintenance; MYCN amplification and upstream TERT rearrangements drive high levels of telomerase expression whereas ALT is a telomerase independent telomere maintenance mechanism. As all three telomere maintenance mechanisms are independently associated with poor outcomes, the development of strategies to selectively target either telomerase expressing or ALT cells holds great promise as a therapeutic approach that is applicable to the majority of children with aggressive disease.Here we summarise the biology of telomere maintenance and the molecular drivers of aggressive neuroblastoma before describing the most promising therapeutic strategies to target both telomerase expressing and ALT cancers. For telomerase-expressing neuroblastoma the most promising targeted agent to date is 6-thio-2'-deoxyguanosine, however clinical development of this agent is required. In osteosarcoma cell lines with ALT, selective sensitivity to ATR inhibition has been reported. However, we present data showing that in fact ALT neuroblastoma cells are more resistant to the clinical ATR inhibitor AZD6738 compared to other neuroblastoma subtypes. More recently a number of additional candidate compounds have been shown to show selectivity for ALT cancers, such as Tetra-Pt (bpy), a compound targeting the telomeric G-quadruplex and pifithrin-α, a putative p53 inhibitor. Further pre-clinical evaluation of these compounds in neuroblastoma models is warranted.In summary, telomere maintenance targeting strategies offer a significant opportunity to develop effective new therapies, applicable to a large proportion of children with high-risk neuroblastoma. In parallel to clinical development, more pre-clinical research specifically for neuroblastoma is urgently needed, if we are to improve survival for this common poor outcome tumour of childhood.
The conserved Rap1 protein is part of the shelterin complex that plays critical roles in chromosome end protection and telomere length regulation. Previous studies have addressed how fission yeast ...Rap1 contributes to telomere length maintenance, but the mechanism by which the protein inhibits end fusions has remained elusive. Here, we use a mutagenesis screen in combination with high‐throughput sequencing to identify several amino acid positions in Rap1 that have key roles in end protection. Interestingly, mutations at these sites render cells susceptible to genome instability in a conditional manner, whereby longer telomeres are prone to undergoing end fusions, while telomeres within the normal length range are sufficiently protected. The protection of long telomeres is in part dependent on their nuclear envelope attachment mediated by the Rap1–Bqt4 interaction. Our data demonstrate that long telomeres represent a challenge for the maintenance of genome integrity, thereby providing an explanation for species‐specific upper limits on telomere length.
Synopsis
Mutational analysis of the shelterin component Rap1 in fission yeast addresses its role beyond telomere length maintenance in protecting from chromosomal end fusions. Surprisingly, this reveals that long telomeres are vulnerable to undergoing end fusions, challenging the view that only critically short telomeres are at risk of being mistaken for DNA breaks.
Rap1 functions in telomere length regulation and end protection.
Mutagenesis screen identifies key residues for protecting telomeres against end fusions.
Long telomeres are more prone to end fusions than normal length telomeres.
Nuclear envelope attachment is critical for the protection of long telomeres.
Mutational analysis of shelterin component Rap1 reveals the vulnerability of long telomeres to undergoing end fusions, challenging the view that only critically short telomeres are at risk of being mistaken for DNA breaks.
Alternative lengthening of telomeres (ALT), a telomerase-independent process maintaining telomeres, is mediated by break-induced replication (BIR). RAD52 promotes ALT by facilitating D-loop ...formation, but ALT also occurs through a RAD52-independent BIR pathway. Here, we show that the telomere non-coding RNA TERRA forms dynamic telomeric R-loops and contributes to ALT activity in RAD52 knockout cells. TERRA forms R-loops in vitro and at telomeres in a RAD51AP1-dependent manner. The formation of R-loops by TERRA increases G-quadruplexes (G4s) at telomeres. G4 stabilization enhances ALT even when TERRA is depleted, suggesting that G4s act downstream of R-loops to promote BIR. In vitro, the telomeric R-loops assembled by TERRA and RAD51AP1 generate G4s, which persist after R-loop resolution and allow formation of telomeric D-loops without RAD52. Thus, the dynamic telomeric R-loops formed by TERRA and RAD51AP1 enable the RAD52-independent ALT pathway, and G4s orchestrate an R- to D-loop switch at telomeres to stimulate BIR.
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•TERRA and RAD51AP1 contribute to the ALT activity in RAD52 KO cells•RAD51AP1 promotes telomeric R-loop formation in vitro and in ALT+ cells•Telomeric R-loops increase G4s at telomeres and are dynamic in cells•Telomeric G4s persist without R-loops and enable D-loop formation without RAD52
Alternative lengthening of telomere (ALT) occurs through RAD52-dependent and -independent break-induced replication (BIR). Yadav et al. show that RAD51AP1 and the telomeric non-coding RNA TERRA promote RAD52-independent ALT by forming dynamic R-loops and increasing G4s at telomeres, enabling an R- to D-loop switch to initiate BIR independently of RAD52.
Telomere shortening is a presumed tumor suppressor pathway that imposes a proliferative barrier (the Hayflick limit) during tumorigenesis. This model predicts that excessively long somatic telomeres ...predispose to cancer. Here, we describe cancer-prone families with two unique
mutations that truncate TIN2, a shelterin subunit that controls telomere length. Patient lymphocyte telomeres were unusually long. We show that the truncated TIN2 proteins do not localize to telomeres, suggesting that the mutations create loss-of-function alleles. Heterozygous knock-in of the mutations or deletion of one copy of
resulted in excessive telomere elongation in clonal lines, indicating that
is haploinsufficient for telomere length control. In contrast, telomere protection and genome stability were maintained in all heterozygous clones. The data establish that the
truncations predispose to a tumor syndrome. We conclude that
acts as a haploinsufficient tumor suppressor that limits telomere length to ensure a timely Hayflick limit.
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