Telomere homeostasis in mammalian germ cells: a review

Reig-Viader, Rita; Garcia-Caldés, Montserrat; Ruiz‐Herrera, Aurora

doi:10.1007/s00412-015-0555-4

Cited by 49 publications

(44 citation statements)

References 186 publications

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“…In adult somatic cells, telomeres are composed of large noncoding sequences of approximately 1000–2000 TTAGGG tandem base pair repeats that end in a 3′ extension past the 5′ terminus [2]. In other select cells, the telomeres are maintained and can be considerably longer, such as adult human germ cells which can contain anywhere from 500–5000 repeats [3,4,5]. During each cycle of cell division telomeres are incompletely replicated, and consequently, their ends are progressively shortened [6].…”

Section: Introductionmentioning

confidence: 99%

Treating Cancer by Targeting Telomeres and Telomerase

et al. 2017

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Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Human telomerase primarily consists of two main components: hTERT, a catalytic subunit, and hTR, an RNA template whose sequence is complimentary to the telomeric 5′-dTTAGGG-3′ repeat. In humans, telomerase activity is typically restricted to renewing tissues, such as germ cells and stem cells, and is generally absent in normal cells. While hTR is constitutively expressed in most tissue types, hTERT expression levels are low enough that telomere length cannot be maintained, which sets a proliferative lifespan on normal cells. However, in the majority of cancers, telomerase maintains stable telomere length, thereby conferring cell immortality. Levels of hTERT mRNA are directly related to telomerase activity, thereby making it a more suitable therapeutic target than hTR. Recent data suggests that stabilization of telomeric G-quadruplexes may act to indirectly inhibit telomerase action by blocking hTR binding. Telomeric DNA has the propensity to spontaneously form intramolecular G-quadruplexes, four-stranded DNA secondary structures that are stabilized by the stacking of guanine residues in a planar arrangement. The functional roles of telomeric G-quadruplexes are not completely understood, but recent evidence suggests that they can stall the replication fork during DNA synthesis and inhibit telomere replication by preventing telomerase and related proteins from binding to the telomere. Long-term treatment with G-quadruplex stabilizers induces a gradual reduction in the length of the G-rich 3’ end of the telomere without a reduction of the total telomere length, suggesting that telomerase activity is inhibited. However, inhibition of telomerase, either directly or indirectly, has shown only moderate success in cancer patients. Another promising approach of targeting the telomere is the use of guanine-rich oligonucleotides (GROs) homologous to the 3’ telomere overhang sequence (T-oligos). T-oligos, particularly a specific 11-base oligonucleotide (5’-dGTTAGGGTTAG-3’) called T11, have been shown to induce DNA damage responses (DDRs) such as senescence, apoptosis, and cell cycle arrest in numerous cancer cell types with minimal or no cytostatic effects in normal, non-transformed cells. As a result, T-oligos and other GROs are being investigated as prospective anticancer therapeutics. Interestingly, the DDRs induced by T-oligos in cancer cells are similar to the effects seen after progressive telomere degradation in normal cells. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer. However, little is known about their mechanism of action. In this review, we discuss the current understanding of how T-oligos exert their antiproliferative effe...

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Section: Introductionmentioning

confidence: 99%

Treating Cancer by Targeting Telomeres and Telomerase

et al. 2017

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“…Perturbation of these processes can result in the reduction or loss of germ cells, leading to infertility, or in aneuploidy, leading to abortive pregnancies or congenital abnormalities in the newborn. Besides their role in protecting the chromosome ends, telomeres also contribute to the dynamic process of germ cell development (Reig-Viader et al 2016 ; Keefe 2016 ). The following section will focus on recent insights on the role of the telomere structure in germ cell function.…”

Section: Introductionmentioning

confidence: 99%

Telomere chromatin establishment and its maintenance during mammalian development

Tardat

Déjardin

2017

Chromosoma

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Telomeres are specialized structures that evolved to protect the end of linear chromosomes from the action of the cell DNA damage machinery. They are composed of tandem arrays of repeated DNA sequences with a specific heterochromatic organization. The length of telomeric repeats is dynamically regulated and can be affected by changes in the telomere chromatin structure. When telomeres are not properly controlled, the resulting chromosomal alterations can induce genomic instability and ultimately the development of human diseases, such as cancer. Therefore, proper establishment, regulation, and maintenance of the telomere chromatin structure are required for cell homeostasis. Here, we review the current knowledge on telomeric chromatin dynamics during cell division and early development in mammals, and how its proper regulation safeguards genome stability.

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“…While at one time it was thought that germ cells do not show telomere attrition, it is now known that this is not the case, at least for mammalian oocytes, where telomere attrition appears to play a central role in oocyte ageing [98]. In mice and humans, oocytes have shorter telomere lengths than sperm, and oocyte telomeres are among the shortest in the body, while those of sperm are among the longest [91,96,97,99]. This is consistent with levels of telomerase being low in oocytes but high in spermatogonia, although the generality of these patterns is unknown [92,99].…”

Section: (B) Telomere Attrition In the Germlinementioning

confidence: 99%

The deteriorating soma and the indispensable germline: gamete senescence and offspring fitness

2019

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The idea that there is an impenetrable barrier that separates the germline and soma has shaped much thinking in evolutionary biology and in many other disciplines. However, recent research has revealed that the so-called ‘Weismann Barrier’ is leaky, and that information is transferred from soma to germline. Moreover, the germline itself is now known to age, and to be influenced by an age-related deterioration of the soma that houses and protects it. This could reduce the likelihood of successful reproduction by old individuals, but also lead to long-term deleterious consequences for any offspring that they do produce (including a shortened lifespan). Here, we review the evidence from a diverse and multidisciplinary literature for senescence in the germline and its consequences; we also examine the underlying mechanisms responsible, emphasizing changes in mutation rate, telomere loss, and impaired mitochondrial function in gametes. We consider the effect on life-history evolution, particularly reproductive scheduling and mate choice. Throughout, we draw attention to unresolved issues, new questions to consider, and areas where more research is needed. We also highlight the need for a more comparative approach that would reveal the diversity of processes that organisms have evolved to slow or halt age-related germline deterioration.

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Telomere homeostasis in mammalian germ cells: a review

Cited by 49 publications

References 186 publications

Treating Cancer by Targeting Telomeres and Telomerase

Treating Cancer by Targeting Telomeres and Telomerase

Telomere chromatin establishment and its maintenance during mammalian development

The deteriorating soma and the indispensable germline: gamete senescence and offspring fitness

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