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

Published

Journal Article

MutLα (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 MutLα 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 MutLα 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 MutLα but not by MutSα (MSH2-MSH6 heterodimer) and that MutLα reversal depends on integrity of the endonuclease active site. Exogenous MutLα also partially rescues the mismatch repair defect in nuclear extract prepared from cells exposed to cadmium. These findings indicate that targeted inhibition of MutLα endonuclease contributes to cadmium inhibition of mismatch repair. This effect may play a role in the mechanism of cadmium carcinogenesis.

Full Text

Duke Authors

Cited Authors

  • Sherrer, SM; Penland, E; Modrich, P

Published Date

  • July 10, 2018

Published In

Volume / Issue

  • 115 / 28

Start / End Page

  • 7314 - 7319

PubMed ID

  • 29941579

Pubmed Central ID

  • 29941579

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1807319115

Language

  • eng

Conference Location

  • United States