MMS1 protects against replication-dependent DNA damage in Saccharomyces cerevisiae

Abstract.

A series of yeast mutants were isolated that are sensitive to killing by the monofunctional DNA-alkylating agent methyl methanesulfonate (MMS) but not by UV or X-radiation. We have cloned and characterized one of the corresponding genes, MMS1, and show that the mms1 Δ mutant is dramatically sensitive to killing by MMS and mildly sensitive to UV radiation. mms1 Δ mutants display an elevated level of spontaneous DNA damage and genomic instability. Furthermore, the mms1 Δ cells are sensitive to killing by conditions that induce replication-dependent double-strand breaks, such as treatment with camptothecin, and incubation of a cdc2-2 strain at the restrictive temperature. rad52 Δ is epistatic to mms1 Δ for MMS and camptothecin sensitivity, indicating that Mms1 acts in concert with Rad52. However, unlike mutants of the RAD52 group, mms1 Δ cells are not sensitive to γ-rays, which induce double-strand breaks independently of DNA replication. Together these results suggest a role for an Mms1-dependent, Rad52-mediated, pathway in protecting cells against replication-dependent DNA damage.