Telomere-driven mutational processes in yeast

Henninger, Erin; Teixeira, Maria Teresa

doi:10.1016/j.gde.2020.02.018

Cited by 9 publications

(9 citation statements)

References 69 publications

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“…The geometric law governing the number of consecutive arrests for a range of thresholds D consistent with repair kinetics supports a model whereby early arrested cells undergo adaptation until the damage is repaired. Since adaptation promotes genome instability by forcing mitosis despite unrepaired DNA damage and lineages retain significant proliferation potential after non-terminal arrests, we speculate that these early arrests might contribute to the mutations and genome rearrangements observed in senescent cultures [ 8 , 11 , 14 , 20 ]. In contrast, cell cycles in the senescence phase end with an extremely long final arrest and cell death.…”

Section: Discussionmentioning

confidence: 99%

“…We speculate that the recruitment of these kinases might also entail some level of stochasticity, which might depend on variable resection and exposure of single-stranded DNA. Another source of variability affecting the signalling capacity of telomeres could also come from the chromatin status of each telomere, as exemplified by the silencing and telomere position effect on transcription of subtelomeric genes and/or the histone levels near telomeres that are known to be affected in senescence [ 20 , 29 ]. Therefore, we suggest that the critical length threshold for the shortest telomere might be probabilistic.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…Budding yeast has been utilized as a model of replicative lifespan regulations in eukaryotic cells. In telomere biology, at least three features are common between budding yeast and human cells: 1) The telomerase deficiency induces senescence in budding yeast (32), 2) Telomere shortening causes senescence via permanent activation of DNA damage checkpoints both in budding yeast and human cells (33), and 3) Telomere shortening-dependent DNA damage checkpoints can be bypassed due to adaptation both in human cells and budding yeast (34, 35). Thus, yeast can serve as a model to study basic senescence mechanisms associated with cell cycle regulations.…”

Section: Discussionmentioning

confidence: 99%

“…Telomere shortening causes senescence via permanent activation of DNA damage checkpoints both in budding yeast and human cells (33), and 3) Telomere shortening-dependent DNA damage checkpoints can be bypassed due to adaptation both in human cells and budding yeast (34,35). Thus, yeast can serve as a model to study basic senescence mechanisms associated with cell cycle regulations.…”

Section: Budding Yeast and Human Cells Share Part Of Stress-dependent...mentioning

confidence: 99%

Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts

Kono

Johmura

Moriyama

et al. 2021

Preprint

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Plasma membrane damage (PMD) occurs in all cell types due to environmental perturbation and cell-autonomous activities. However, cellular outcomes of PMD remain largely unknown except for recovery or death. Here, using yeast and human fibroblasts, we show that cellular senescence, irreversible cell cycle arrest contributing to organismal aging, is the third outcome of PMD. To identify the genes essential for PMD response, we performed a systematic yeast genome-wide screen. The screen identified 48 genes. The top hits in the screen are the endosomal sorting complexes required for transport (ESCRT) genes. Strikingly, the replicative lifespan regulator genes are enriched in our 48 hits, and indeed, PMD limits the replicative lifespan in budding yeast; the ESCRT activator AAA-ATPase VPS4-overexpression extends it. In normal human fibroblasts, PMD induces cellular senescence via p53. Our study demonstrates that PMD limits replicative lifespan in two different eukaryotic cell types and highlights an underappreciated but ubiquitous senescent cell subtype, namely PMD-dependent senescent cells.

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“…We speculate that the recruitment of these kinases might also entail some level of stochasticity, which might depend on variable resection and exposure of single-stranded DNA. Another source of variability affecting the signalling capacity of telomeres could also come from the chromatin status of each telomere, as exemplified by the silencing and telomere position effect on transcription of subtelomeric genes and/or the histone levels near telomeres that are known to be affected in senescence (20,29). Therefore, we suggest that the critical length threshold for the shortest telomere might be probabilistic.…”

Section: Discussionmentioning

confidence: 99%

Telomere shortening causes distinct cell division regimes during replicative senescence inSaccharomyces cerevisiae

Martin¹,

Doumic

Teixeira

et al. 2021

Preprint

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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.

show abstract

Telomere-driven mutational processes in yeast

Cited by 9 publications

References 69 publications

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

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

Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts

Telomere shortening causes distinct cell division regimes during replicative senescence inSaccharomyces cerevisiae

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