title: The asymmetry of telomere replication contributes to replicative senescence heterogeneity.
abstract: In eukaryotes, the absence of telomerase results in telomere shortening, eventually leading to replicative senescence, an arrested state that prevents further cell divisions. While replicative senescence is mainly controlled by telomere length, the heterogeneity of its onset is not well understood. This study proposes a mathematical model based on the molecular mechanisms of telomere replication and shortening to decipher the causes of this heterogeneity. Using simulations fitted on experimental data obtained from individual lineages of senescent Saccharomyces cerevisiae cells, we decompose the sources of senescence heterogeneity into interclonal and intraclonal components, and show that the latter is based on the asymmetry of the telomere replication mechanism. We also evidence telomere rank-switching events with distinct frequencies in short-lived versus long-lived lineages, revealing that telomere shortening dynamics display important variations. Thus, the intrinsic heterogeneity of replicative senescence and its consequences find their roots in the asymmetric structure of telomeres.
authors.affiliation: INRIA Paris-Rocquencourt, Domaine de Voluceau, BP 105, 78153 Le Chesnay, France. UPMC University of Paris 6, JL Lions Lab., 4 place Jussieu, 75005 Paris, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Bourgeron
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CNRS, 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: INRIA Paris-Rocquencourt, Domaine de Voluceau, BP 105, 78153 Le Chesnay, France. UPMC University of Paris 6, JL Lions Lab., 4 place Jussieu, 75005 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Doumic
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, CNRS, 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: D016922:Cellular Senescence; D004271:DNA, Fungal / Q000235:genetics / Q000378:metabolism; D008962:Models, Theoretical; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D016615:Telomere / Q000378:metabolism*; D059506:Telomere Shortening
chemical_list: D004271:DNA, Fungal; D029701:Saccharomyces cerevisiae Proteins