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

ABSTRACT: Alkylation chemotherapy is commonly used against tumors such as glioblastoma, yet resistance often develops through downregulation of mismatch repair (MMR). Previous work has established that loss of MMR prevents the excision of the thymine-containing strand across O ⁶meG-T mismatches. Thus, MMR dysfunction is advantageous because it prevents a vicious cycle of attempted repair that leads to cell death. Here, we provide an alternative explanation to this prevailing mechanism of alkylation chemoresistance by MMR loss. We find that the MMR protein MutLα physically and functionally interacts with the base excision repair (BER) enzyme methylpurine DNA glycosylase (MPG), which processes common alkylation adducts, such as 7meG and 3meA. Biochemical reconstitution demonstrates t

SUBMITTER: Ashour ME 

PROVIDER: S-EPMC12724163 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature