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Telomere shortening causes distinct cell division regimes during replicative senescence in Saccharomyces cerevisiae.

TitleTelomere shortening causes distinct cell division regimes during replicative senescence in Saccharomyces cerevisiae.
Publication TypeJournal Article
Year of Publication2021
AuthorsMartin, H, Doumic, M, Teixeira, MTeresa, Xu, Z
JournalCell Biosci
Date Published2021 Oct 09

BACKGROUND: Telomerase-negative cells have limited proliferation potential. In these cells, telomeres shorten until they reach a critical length and induce a permanently arrested state. This process called replicative senescence is associated with genomic instability and participates in tissue and organismal ageing. Experimental data using single-cell approaches in the budding yeast model organism show that telomerase-negative cells often experience abnormally long cell cycles, which can be followed by cell cycles of normal duration, before reaching the terminal senescent state. These series of non-terminal cell cycle arrests contribute to the heterogeneity of senescence and likely magnify its genomic instability. Due to their apparent stochastic nature, investigating the dynamics and the molecular origins of these arrests has been difficult. In particular, whether the non-terminal arrests series stem from a mechanism similar to the one that triggers terminal senescence is not known.

RESULTS: Here, we provide a mathematical description of sequences of non-terminal arrests to understand how they appear. We take advantage of an experimental data set of cell cycle duration measurements performed in individual telomerase-negative yeast cells that keep track of the number of generations since telomerase inactivation. Using numerical simulations, we show that the occurrence of non-terminal arrests is a generation-dependent process that can be explained by the shortest telomere reaching a probabilistic threshold length. While the onset of senescence is also triggered by telomere shortening, we highlight differences in the laws that describe the number of consecutive arrests in non-terminal arrests compared to senescence arrests, suggesting distinct underlying mechanisms and cellular states.

CONCLUSIONS: Replicative senescence is a complex process that affects cell divisions earlier than anticipated, as exemplified by the frequent occurrence of non-terminal arrests early after telomerase inactivation. The present work unravels two kinetically and mechanistically distinct generation-dependent processes underlying non-terminal and terminal senescence arrests. We suggest that these two processes are responsible for two consequences of senescence at the population level, the increase of genome instability on the one hand, and the limitation of proliferation capacity on the other hand.

Alternate JournalCell Biosci
PubMed ID34627377
Grant ListANR-17-CE20-0002-01 / / agence nationale de la recherche /
LabEx Dynamo ANR-11-LABX-0011-01 / / agence nationale de la recherche /
ANR-16-CE12-0026 / / agence nationale de la recherche /
Programme Émergence(s) / / ville de paris /
Équipe FRM EQU202003010428 / / fondation pour la recherche médicale /
INCa_15192 / / institut national du cancer /