title: Two routes to senescence revealed by real-time analysis of telomerase-negative single lineages.
abstract: In eukaryotes, telomeres cap chromosome ends to maintain genomic stability. Failure to maintain telomeres leads to their progressive erosion and eventually triggers replicative senescence, a pathway that protects against unrestricted cell proliferation. However, the mechanisms underlying the variability and dynamics of this pathway are still elusive. Here we use a microfluidics-based live-cell imaging assay to investigate replicative senescence in individual Saccharomyces cerevisiae cell lineages following telomerase inactivation. We characterize two mechanistically distinct routes to senescence. Most lineages undergo an abrupt and irreversible switch from a replicative to an arrested state, consistent with telomeres reaching a critically short length. In contrast, other lineages experience frequent and stochastic reversible arrests, consistent with the repair of accidental telomere damage by Pol32, a subunit of polymerase δ required for break-induced replication and for post-senescence survival. Thus, at the single-cell level, replicative senescence comprises both deterministic cell fates and chaotic cell division dynamics.
authors.affiliation: 1] Centre National de la Recherche Scientifique, UMR8226, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, Institut de Biologie Physico-Chimique, 75005 Paris, France [2] Sorbonne Universités, UPMC University Paris 06, UMR8226, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, Institut de Biologie Physico-Chimique, 75005 Paris, France.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xu
authors.affiliation: 1] Centre National de la Recherche Scientifique, UMR8226, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, Institut de Biologie Physico-Chimique, 75005 Paris, France [2] Sorbonne Universités, UPMC University Paris 06, UMR8226, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, Institut de Biologie Physico-Chimique, 75005 Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Fallet
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, Illkirch, 67400, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Paoletti
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, Illkirch, 67400, France.
authors.forename: Steffen
authors.initials: S
authors.lastname: Fehrmann
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, Illkirch, 67400, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Charvin
authors.affiliation: 1] Centre National de la Recherche Scientifique, UMR8226, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, Institut de Biologie Physico-Chimique, 75005 Paris, France [2] Sorbonne Universités, UPMC University Paris 06, UMR8226, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, Institut de Biologie Physico-Chimique, 75005 Paris, France.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Teixeira
mesh_terms: D015139:Blotting, Southern; D059447:Cell Cycle Checkpoints; D002455:Cell Division; D019070:Cell Lineage; D053960:DNA Breaks; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D056656:Lab-On-A-Chip Devices; D008856:Microscopy, Fluorescence; D008858:Microscopy, Phase-Contrast; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000378:metabolism*; D059506:Telomere Shortening; D059008:Time-Lapse Imaging
chemical_list: C522758:Pol32 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D019098:Telomerase; D004259:DNA-Directed DNA Polymerase