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How telomeres control cell proliferation


Replication of the ends of linear chromosomes of eukaryotes results in progressive sequence loss at each cell division, a process counteracted by telomerase. In its absence, telomeres reach a short length and induce replicative senescence to control organ homeostasis. This equilibrium is disrupted in cancer cells, as well as in patients suffering from a wide spectrum of degenerative syndromes. Still, progress in understanding telomere replication and its relationship to senescence has been hampered by intrinsic variations in telomeres and the stochastic nature of senescence onset. Work in our lab builds on our ability to experimentally circumvent and dissect the causes of such heterogeneity. Our strategy is to manipulate and track single telomeres in individual cells and experimentally evaluate the effects on the proliferation potential of single cell lineages to build a mathematical model of senescence. We set up a microfluidics-based live-cell imaging assay to investigate replicative senescence in individual Saccharomyces cerevisiae cell lineages following telomerase inactivation. We found that most lineages experience an abrupt and irreversible transition consistent with a mathematical model where the first telomere reaching a critical short length triggers senescence onset. However, many lineages undergo frequent reversible DNA damage checkpoint cell-cycle arrests, beginning soon after telomerase inactivation. This novel phenotype likely stems from replicative stress at telomeres and gives rise to genomic instability. We have further demonstrated that “adaptation to DNA damage” pathway allows cell divisions despite the presence of unrepaired telomeric damage. Adaptation is thus a major contributor to heterogeneity and genome instability induced in replicative senescence. In sum, senescence is composed of two kinetically and mechanistically distinct age-dependent processes underlying non-terminal and terminal senescence arrests. We suggest that these two processes might be responsible for different aspects of senescence at the population level, such as genome instability and loss of proliferation.
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Dates and versions

hal-04024221 , version 1 (10-03-2023)


  • HAL Id : hal-04024221 , version 1


Maria Teresa Teixeira. How telomeres control cell proliferation. 2020 QBI/PSL-Qlife symposium, Dec 2020, Paris, France. ⟨hal-04024221⟩
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