The SRS2 gene encodes a helicase that affects recombination, gene conversion and DNA damage repair in the yeast Saccharomyces cerevisiae. Loss-of-function mutations in srs2 suppress the extreme sensitivity towards UV radiation of rad6 and rad18 mutants, both of which are impaired in post-replication DNA repair and damage-induced mutagenesis. A sub-branch within the RAD6 pathway is mediated by RAD5, UBC13 and MMS2, and a comprehensive analysis of the srs2 effect on other known members of the RAD6 pathway reported here now demonstrates that suppression by srs2 is specific for mutants within this RAD5-dependent sub-system. Further evidence for the concerted action of RAD5 with UBC13 and MMS2 in DNA damage repair is given by examination of the effects of cell cycle stage as well as deletion of other repair systems on the activity of post-replication repair. Finally, it is shown that MMS2, like UBC13 and many other repair genes, is transcriptionally up-regulated in response to DNA damage. The data presented here support the notion that RAD5, UBC13 and MMS2 encode an ensemble of genetically and physically interacting repair factors within the RAD6 pathway that is coordinately affected by SRS2.