Proficient repair in chromatin remodeling defective ino80 mutants of Saccharomyces cerevisiae highlights replication defects as the main contributor to DNA damage sensitivity

Ino80 is an evolutionarily conserved member of the SWI2/SNF2-family of ATPases in Saccharomyces cerevisiae. It resides in a multiprotein helicase/chromatin remodeling complex, and has been shown to play a key role in the stability of replication forks during replication stress. Though yeast with defects in ino80 show sensitivity to killing by a variety of DNA-damaging agents, a role for the INO80 protein complex in the repair of DNA has only been assessed for double-strand breaks, and the results are contradictory and inconclusive. We report that ino80Δ cells are hypersensitive to DNA base lesions induced by ultraviolet (UV) radiation and methyl methanesulfonate (MMS), but show little (or no) increased sensitivity to the DNA double-strand break (DSB)-inducing agents ionizing radiation and camptothecin. Importantly, ino80Δ cells display efficient removal of UV-induced cyclobutane pyrimidine dimers, and show a normal rate of removal of DNA methylation damage after MMS exposure. In addition, ino80Δ cells have an overall normal rate of repair of DSBs induced by ionizing radiation. Altogether, our data support a model of INO80 as an important suppressor of genome instability in yeast involved in DNA damage tolerance through a role in stability and recovery of broken replication forks, but not in the repair of lesions leading to such events. This conclusion is in contrast to strong evidence for the DNA repair-promoting role of the corresponding INO80 complexes in higher eukaryotes. Thus, our results provide insight into the specialized roles of the INO80 subunits and the differential needs of different species for chromatin remodeling complexes in genome maintenance.