Complex interactions between the DNA-damage response and mammalian telomeres


Natural chromosome ends resemble double-stranded DNA breaks, but they do not activate a damage response in healthy cells. Telomeres therefore have evolved to solve the 'end-protection problem' by inhibiting multiple DNA damage–response pathways. During the past decade, the view of telomeres has progressed from simple caps that hide chromosome ends to complex machineries that have an active role in organizing the genome. Here we focus on mammalian telomeres and summarize and interpret recent discoveries in detail, focusing on how repair pathways are inhibited, how resection and replication are controlled and how these mechanisms govern cell fate during senescence, crisis and transformation.

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Figure 1: Repression of DNA-damage signaling pathways at telomeres.
Figure 2: Functions and interactions of TRF2 domains.
Figure 3: Major DNA-repair factors involved in telomere maintenance during S phase.
Figure 4: Replicative senescence and crisis are two proliferative barriers controlled by telomere deprotection.


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N.A. is supported by the Human Frontier Science Program (LT000284/2013). J.K. is supported by a Salk Institute Cancer Center Core Grant (P30CA014195), the US National Institutes of Health (R01GM087476 and R01CA174942), the Donald and Darlene Shiley Chair, the Highland Street Foundation, the Fritz B. Burns Foundation, the Emerald Foundation and the Glenn Center for Research on Aging.

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Arnoult, N., Karlseder, J. Complex interactions between the DNA-damage response and mammalian telomeres. Nat Struct Mol Biol 22, 859–866 (2015).

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