The mutagen and carcinogen cadmium is a high-affinity inhibitor of the zinc-dependent MutL? endonuclease.

ABSTRACT: MutL? (MLH1-PMS2 heterodimer), which acts as a strand-directed endonuclease during the initiation of eukaryotic mismatch repair, has been postulated to function as a zinc-dependent enzyme [Kosinski J, Plotz G, Guarné A, Bujnicki JM, Friedhoff P (2008) J Mol Biol 382:610-627]. We show that human MutL? copurifies with two bound zinc ions, at least one of which resides within the endonuclease active site, and that bound zinc is required for endonuclease function. Mutagenic action of the carcinogen cadmium, a known inhibitor of zinc-dependent enzymes, is largely due to selective inhibition of mismatch repair [Jin YH, et al. (2003) Nat Genet 34:326-329]. We show that cadmium is a potent inhibitor (apparent Ki ? 200 nM) of MutL? endonuclease and that cadmium inhibition is reversed by zinc. We also show that inhibition of mismatch repair in cadmium-treated nuclear extract is significantly reversed by exogenous MutL? but not by MutS? (MSH2-MSH6 heterodimer) and that MutL? reversal depends on integrity of the endonuclease active site. Exogenous MutL? also partially rescues the mismatch repair defect in nuclear extract prepared from cells exposed to cadmium. These findings indicate that targeted inhibition of MutL? endonuclease contributes to cadmium inhibition of mismatch repair. This effect may play a role in the mechanism of cadmium carcinogenesis.

SUBMITTER: Sherrer SM 

PROVIDER: S-EPMC6048502 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature