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1. How the shortest telomere in the cell signals senescence

Author

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

2. How the shortest telomere in the cell signals senescence

Author

Mattarocci, Stefano, Berardi, Prisca, Langston, Rachel, Marcand, Stéphane, 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 Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, 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), INCa : PLBIO16-059, FRM: EQU202003010428, Ligue Contre Le Cancer, Cold Spring Harbor Laboratory, 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; Telomeres ensure genome integrity and are maintained by telomerase. During replicative senescence, telomerase is inactivated, telomere sequences progressively shorten and set the limit for cell proliferation. When telomeres shorten, they are thought to lose their protective caps at a critical short length, which activates the DNA damage response and recruits 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 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 in Saccharomyces cerevisiae a system called FinalCut to induce a single telomere of defined length in cells in which we can conditionally inactivate telomerase. This allows structural analysis of this telomere and, combined with the use of our microfluidic system to track consecutive cell cycles from telomerase inactivation to cell death, we can achieve single telomere and single cell resolution. Our results show that cells reach senescence earlier and more synchronously, as the shortest telomere is set at a shorter length. This is in agreement with the first telomere reaching a short length being sufficient to trigger senescence in budding yeast. Below a certain threshold, the shorter telomere becomes unstable and degrades. However, we can define a length for which a short telomere appears to be stable, and the cells stop dividing at the same time. Combined with a mathematical model of senescence, our results suggest that the probability of a telomere signaling senescence increases as it shortens, but at low frequencies. When a telomere reaches a critical length, it can be stably maintained in cells, while activating the DNA damage checkpoint, without causing obvious fusions or degradation. The structure of this critically short telomere will be discussed.

Published
2021

3. The effect of the shortest telomere on cell proliferation

Author

Mattarocci, Stefano, Berardi, Prisca, Langston, Rachel, Marcand, Stéphane, 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), Department of Molecular and Cellular Biology [University of Arizona], University of Arizona, Radiobiologie moléculaire et cellulaire (RMC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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), INCa : PLBIO16-059, FRM: EQU202003010428, Ligue Contre Le Cancer, Cold Spring Habor Laboratory, 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; Progress in understanding telomere replication and its relationship to senescence has been hampered by the intrinsic variations in telomeres and the stochastic nature of senescence onset. The work in our lab relies on our ability to circumvent and experimentally dissect the causes of this heterogeneity. Our strategy is to manipulate and track single telomeres in individual cells and experimentally evaluate the effects on proliferation potential of single cell lines to build a mathematical model of senescence.We therefore set up a microfluidics-based live cell imaging assay to study replicative senescence in single Saccharomyces cerevisiae cell lineages after telomerase inactivation. We found that most lineages undergo an abrupt and irreversible transition consistent with a mathematical model in which the first telomere reaching a short critical length triggers the onset of senescence. Other cells exhibit transient checkpoint-dependent cell cycle delays followed by normal cell cycles before senescence. We have now shown that these two pathways to senescence correspond to two kinetically and mechanistically distinct, age-dependent processes underlying non- terminal and terminal senescence arrest.Taking advantage of our novel FinalCut system, we also investigated the proliferation potential of telomerase-negative cells with critically short telomeres of different defined lengths. Our results are consistent with a model whereby a small portion of cells may enter senescence in a probabilistic manner as the length of the shortest telomere decreases. Our results thus directly demonstrate that the length of the shortest telomere is a major determinant of entry into senescence, but a hidden parameter may also contribute to the onset of senescence upon telomerase inactivation. However, when the shortest telomere reaches a critical length, all cells immediately arrest. In addition, we found that at this critical length, the shortest telomere can be stably maintained without signs of fusions or degradations. This suggests that telomeres can be both critically short and functional with respect to telomere protection.

Published
2021

4. The shortest telomere in the cell signals senescence through a probabilistic rather than deterministic mechanism

Author

Mattarocci, Stefano, Berardi, Prisca, Langston, Rachel, Jolivet, Pascale, Maes, Alexandre, Marcand, Stéphane, 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), Radiobiologie moléculaire et cellulaire (RMC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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), 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), INCa : PLBIO16-059, FRM: EQU202003010428, La Ligue Contre le Cancer, ANR-11-LABX-0011,DYNAMO,Dynamique des membranes transductrices d'énergie : biogénèse et organisation supramoléculaire.(2011), and ANR-16-CE12-0026,InTelo,Comment la prolifération cellulaire est contrôlée par les télomères: une approche à l'échelle de lignée cellulaire individuelle(2016)

Subjects
[SDV.GEN]Life Sciences [q-bio]/Genetics, Telomeres, [SDV]Life Sciences [q-bio], DNA repair, [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], Telomerase
Abstract

International audience; Telomeres ensure genome integrity and are maintained by telomerase. During replicative senescence, telomerase is inactivated, telomere sequences progressively shorten, and set the limit for cell proliferation. As 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 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 developed a system called FinalCut to induce a single telomere of defined length in cells in which we can conditionally inactivate telomerase. This allows structural analysis of this telomere, and combined with the use of our microfluidic system to track consecutive cell cycles from telomerase inactivation to cell death, we can achieve single telomere and single cell resolution. Our results show that the loss of telomere stability is progressive as the telomere shortens, and that telomeres of a given length can be protected or unprotected in separate cells. We conclude that telomere length is not the sole determinant of the switch between functional and dysfunctional telomeres. We therefore propose that the minimum length of telomeres to maintain cell viability follows a probabilistic, rather than deterministic, model.

Published
2021

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