Human MutLα activates methylpurine DNA glycosylase to induce alkylation damage cytotoxicity.

MutLα activates methylpurine DNA glycosylase to promote alkylation damage cytotoxicity, revealing a new cross-talk between mismatch repair and base excision repair.

• Why it matters: Understanding mechanisms of chemoresistance in alkylation therapy is crucial, especially since loss of mismatch repair (MMR) often confers resistance in tumors like glioblastoma. This work addresses the gap in knowledge about how MMR influences alkylation damage response beyond its role in mismatch recognition.
• What they did: The study examined the interaction between MutLα and MPG through biochemical reconstitution and cellular assays, demonstrating that MutLα enhances MPG activity via ATP hydrolysis and its MLH1-interacting region, leading to increased abasic sites upon alkylation.
• The result: MutLα's activation of MPG increases alkylation-induced abasic sites, contributing to methyl methanesulfonate cytotoxicity, and suggests that MMR-BER cross-talk influences alkylation chemoresistance mechanisms.