In Saccharomyces cerevisiae, a DNA damage checkpoint in the S-phase is responsible for delaying DNA replication in response to genotoxic stress. This pathway is partially regulated by the checkpoint proteins Rad9, Rad17 and Rad24. Here, we describe a novel hypermutable phenotype for rad9Delta, rad17Delta and rad24Delta cells in response to a chronic 0.01% dose of the DNA alkylating agent MMS. We report that this hypermutability results from DNA damage introduction during the S-phase and is dependent on a functional translesion synthesis pathway. In addition, we performed a genetic screen for interactions with rad9Delta that confer sensitivity to 0.01% MMS. We report and quantify 25 genetic interactions with rad9Delta, many of which involve the post-replication repair machinery. From these data, we conclude that defects in S-phase checkpoint regulation lead to increased reliance on mutagenic translesion synthesis, and we describe a novel role for members of the S-phase DNA damage checkpoint in suppressing mutagenic post-replicative repair in response to sublethal MMS treatment.

• PMID: 20472512
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Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov't

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Murakami-Sekimata A, Huang D, Piening BD, Bangur C, Paulovich AG

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