期刊
NUCLEIC ACIDS RESEARCH
卷 49, 期 20, 页码 11690-11707出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab965
关键词
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资金
- Institut du Cancer de Montreal
- Universite de Montreal
- McGill University
- Canadian Institutes of Health Research [MOP114962]
- Natural Sciences and Engineering Research Council of Canada [22624, 33070]
- Mitacs
Loss of telomeric DNA leads to telomere uncapping and triggers a persistent, p53-centric DNA damage response that sustains a stable senescence-associated proliferation arrest. Dysfunction of telomeres during cell division results in sporadic telomeric sister chromatid fusions and genome instability, ultimately leading to senescence mediated by p53. Blocking Rad51/RPA-mediated homologous recombination can prevent senescence despite dysfunctional telomeres, suggesting that repairing telomeres in the pre-senescent state could potentially prevent senescence and genome instability.
Loss of telomeric DNA leads to telomere uncapping, which triggers a persistent, p53-centric DNA damage response that sustains a stable senescence-associated proliferation arrest. Here, we show that in normal cells telomere uncapping triggers a focal telomeric DNA damage response accompanied by a transient cell cycle arrest. Subsequent cell division with dysfunctional telomeres resulted in sporadic telomeric sister chromatid fusions that gave rise to next-mitosis genome instability, including non-telomeric DNA lesions responsible for a stable, p53-mediated, senescence-associated proliferation arrest. Unexpectedly, the blocking of Rad51/RPA-mediated homologous recombination, but not non-homologous end joining (NHEJ), prevented senescence despite multiple dysfunctional telomeres. When cells approached natural replicative senescence, interphase senescent cells displayed genome instability, whereas near-senescent cells that underwent mitosis despite the presence of uncapped telomeres did not. This suggests that these near-senescent cells had not yet acquired irreversible telomeric fusions. We propose a new model for telomere-initiated senescence where tolerance of telomere uncapping eventually results in irreversible non-telomeric DNA lesions leading to stable senescence. Paradoxically, our work reveals that senescence-associated tumor suppression from telomere shortening requires irreversible genome instability at the single-cell level, which suggests that interventions to repair telomeres in the pre-senescent state could prevent senescence and genome instability. [GRAPHICS] .
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