The short life span of Saccharomyces cerevisiae sgs1 and srs2 mutants is acomposite of normal aging processes and mitotic arrest due to defective recombination

Evidence fr om many organisms indicates that the conserved RecQ helicases f unction in the maintenance of genomic stability. Mutation of SGS1 and WRN: which encode RecQ homologues in budding yeast and humans, respectively, res ults ill phenotypes characteristic of premature aging. Mutation of SRS2, an other DNA helicase, causes synthetic slow growth in an sgs1 background. In this work, we demonstrate that srs2 mutants have a shortened life span simi lar to sgs1 mutants. Further dissection of the sgs1 and srs2 survival curve s reveals two distinct phenomena. A majority of sgs1 and srs2 cells stops d ividing stochastically as large-budded cells. This mitotic cell cycle arres t is age independent and requires the RAD9-dependent DNA damage checkpoint. Late-generation sgs1 and srs2 cells senesce due to apparent premature agin g, most likely involving the accumulation of extrachromosomal rDNA circles. Double sgs1 srs2 mutants at e viable but have a high stochastic rate of te rminal G2/M arrest. This arrest cain be suppressed by mutations in RAD51, R AD52, and RAD57, suggesting that the cell cycle defect in sgs1 srs2 mutants results from inappropriate homologous recombination. Finally, mutation of RAD1 or RAD50 exacerbates the growth defect of sgs1 srs2 cells, indicating that sgs1 srs2 mutants may utilize single-strand annealing as an alternativ e repair pathway.