Roles of RAD6 Epistasis Group Members in Spontaneous Polζ-Dependent Translesion Synthesis in Saccharomyces cerevisiae

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Abstract
DNA lesions that arise during normal cellular metabolism can block the progress of replicative DNA polymerases, leading to cell cycle arrest and, in higher eukaryotes, apoptosis. Alternatively, such blocking lesions can be temporarily tolerated using either a recombination- or a translesion synthesis-based bypass mechanism. In Saccharomyces cerevisiae, members of the RAD6 epistasis group are key players in the regulation of lesion bypass by the translesion DNA polymerase Polζ. In this study, changes in the reversion rate and spectrum of the lys2ΔA746 −1 frameshift allele have been used to evaluate how the loss of members of the RAD6 epistasis group affects Polζ-dependent mutagenesis in response to spontaneous damage. Our data are consistent with a model in which Polζ-dependent mutagenesis relies on the presence of either Rad5 or Rad18, which promote two distinct error-prone pathways that partially overlap with respect to lesion specificity. The smallest subunit of Polδ, Pol32, is also required for Polζ-dependent spontaneous mutagenesis, suggesting a cooperative role between Polδ and Polζ for the bypass of spontaneous lesions. A third error-free pathway relies on the presence of Mms2, but may not require PCNA.