A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]²⁺ cluster.

ABSTRACT: The human DNA repair enzyme MUTYH excises mispaired adenine residues in oxidized DNA. Homozygous MUTYH mutations underlie the autosomal, recessive cancer syndrome MUTYH-associated polyposis. We report a MUTYH variant, p.C306W (c.918C>G), with a tryptophan residue in place of native cysteine, that ligates the [4Fe4S] cluster in a patient with colonic polyposis and family history of early age colon cancer. In bacterial MutY, the [4Fe4S] cluster is redox active, allowing rapid localization to target lesions by long-range, DNA-mediated signalling. In the current study, using DNA electrochemistry, we determine that wild-type MUTYH is similarly redox-active, but MUTYH C306W undergoes rapid oxidative degradation of its cluster to [3Fe4S]⁺, with loss of redox signalling. In MUTYH C306W,

SUBMITTER: McDonnell KJ 

PROVIDER: S-EPMC6060025 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature