Interactions of Exo1p with components of MutLα in Saccharomyces cerevisiae

Previously, we reported evidence suggesting that Saccharomyces cerevisiae MutL alpha, composed of Mlh1p and Pms1p, was a functional member of the gyrase b/Hsp90/MutL (GHL) dimeric ATPase superfamily characterized by highly conserved ATPase domains. Similar to other GHL ATPases, these putative ATPase domains of MutL alpha may be important for the recruitment and/or activation of downstream effectors. One downstream effector candidate is Exo1p, a 5 ' -3 ' double stranded DNA exonuclease that has previously been implicated in DNA mismatch repair (MMR). Here we report yeast two-hybrid results suggesting that Exo1p can interact physically with MutLa through the Mlh1p subunit. We also report epistasis ana lysis involving MutLa ATPase mutations combined with exo1 Delta. One interpretation of our genetic results is that MutL alpha ATPase domains function to direct Exo1p and other functionally redundant exonucleases during MMR. Finally, our results show that much of the increase in spontaneous mutation observed in an exo1 Delta strain is REV3-dependent, in turn suggesting that Exo1p is also involved in one or more MMR-independent mutation avoidance pathways.