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Reversibility of replicative senescence inSaccharomyces cerevisiae Effect of homologous recombination and cell cycle checkpoints

Reversibility of replicative senescence inSaccharomyces cerevisiae Effect of homologous recombination and cell cycle checkpoints

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-deficientSaccharomyces cerevisiaecells undergo a similar process, with most cells arresting growth after approximately 6 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 (mec3and/orrad24cells), survival of recombination-defectiverad52mutants remained low after telomerase reactivation. Telomere lengths in rescuedest2cells were initially half those of wildtype cells, but could be restored to normal by propagation for ?7 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.Reversibility of senescence in yeast cells was tested using two approaches. Despite telomere damage, most cells were viable after telomerase reactivation. Mating of senescent cells with normal cells also restored growth capability. Rescue by telomerase differed in checkpoint mutants and recombination mutants. Cells rescued by telomerase exhibited shortened telomeres..

Accession: 036255062

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