Interaction of proliferating cell nuclear antigen with PMS2 is required for MutLα activation and function in mismatch repair

Significance MutLα is required for initiation of eukaryotic mismatch repair. Inactivation of human MutLα is a cause of Lynch syndrome, a common hereditary cancer, and has also been implicated in the development of a subset of sporadic tumors. The proliferating cell nuclear antigen (PCNA) sliding clamp is required for activation and strand direction of the MutLα endonuclease. We show that physical interaction of the two proteins, which form a weak complex in solution, is required for MutLα activation, and have identified a hexapeptide motif within the MutLα PMS2 (PMS1 in yeast) subunit that is required for interaction with PCNA and for MutLα function in mismatch repair. These findings clarify the mechanism of MutLα activation and establish the importance of PCNA interaction in this process.