title: Reversibility of replicative senescence in Saccharomyces cerevisiae: effect of homologous recombination and cell cycle checkpoints.
abstract: Primary human somatic cells grown in culture divide a finite number of times, exhibiting progressive changes in metabolism and morphology before cessation of cycling. This telomere-initiated cellular senescence occurs because cells have halted production of telomerase, a DNA polymerase required for stabilization of chromosome ends. Telomerase-deficient Saccharomyces cerevisiae cells undergo a similar process, with most cells arresting growth after approximately 60 generations. In the current study we demonstrate that senescence is largely reversible. Reactivation of telomerase (EST2) expression in the growth-arrested cells led to resumption of cycling and reversal of senescent cell characteristics. Rescue was also observed after mating of senescent haploid cells with telomerase-proficient cells to form stable diploids. Although senescence was reversible in DNA damage checkpoint response mutants (mec3 and/or rad24 cells), survival of recombination-defective rad52 mutants remained low after telomerase reactivation. Telomere lengths in rescued est2 cells were initially half those of wildtype cells, but could be restored to normal by propagation for ∼70 generations in the presence of telomerase. These results place limitations on possible models for senescence and indicate that most cells, despite gross morphological changes and short, resected telomeres, do not experience lethal DNA damage and become irreversibly committed to death.
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Becerra
authors.forename: Hiranthi T
authors.initials: HT
authors.lastname: Thambugala
authors.forename: Alison Russell
authors.initials: AR
authors.lastname: Erickson
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Lee
authors.forename: L Kevin
authors.initials: LK
authors.lastname: Lewis
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics*; D015825:Chromosomes, Fungal / Q000235:genetics; D015169:Colony Count, Microbial; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D050296:Microbial Viability / Q000235:genetics; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics* / Q000254:growth & development; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D013997:Time Factors
chemical_list: D019098:Telomerase
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