1. How the shortest telomere in the cell signals senescence
- Author
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Berardi, Prisca, Mattarocci, Stefano, Langston, Rachel, Jolivet, Pascale, Charvin, Gilles, Doumic, Marie, Xu, Zhou, Teixeira, Maria Teresa, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes (LBMCE), Institut de biologie physico-chimique (IBPC (FR_550)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modelling and Analysis for Medical and Biological Applications (MAMBA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Biologie Computationnelle et Quantitative = Laboratory of Computational and Quantitative Biology (LCQB), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), FRM: EQU202003010428, Ligue Contre Le Cancer, INCa : PLBIO16-059, EMBO, and ANR-11-LABX-0011,DYNAMO,Dynamique des membranes transductrices d'énergie : biogénèse et organisation supramoléculaire.(2011)
- Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics ,[SDV]Life Sciences [q-bio] ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] - Abstract
International audience; When telomeres shorten, they are thought to lose their protective caps at a critical short length, activating the DNA damage response and recruiting DNA damage repair activities that would degrade, fuse or recombine dysfunctional telomeres. However, the structure(s) of short and dysfunctional telomeres, which respectively trigger permanent replicative senescence and/or potentially promote genome instability, remain unclear.To define the structure of telomeres at the point of dysfunction and the fate of cells carrying them, we have developed a system called FinalCut in Saccharomyces cerevisiae to induce a single telomere of defined length in cells in which we can conditionally inactivate telomerase. This allows 1/ the structural analysis of the shortest telomere in cells, 2/ the monitoring of the pace and the number of consecutive cell cycles from telomerase inactivation to cell death with our microfluidic system, and 3/ the combination of our single cell - single telomere resolved data with a mathematical model of senescence in budding yeast.Our results show that a very small fraction of cells can enter senescence in a probabilistic manner, as cells proliferate in the absence of telomerase. However, for the large majority of cells, when the shortest telomere reaches a critical threshold length, cells immediately stop proliferation. This is consistent with the model that the first telomere reaching a short threshold length is sufficient to abruptly stop cell divisions in a large majority of cells. The structure of this critically short telomere will be discussed.
- Published
- 2022