Structure of human MUTYH and functional profiling of cancer-associated variants reveal an allosteric network between its [4Fe-4S] cluster cofactor and active site required for DNA repair

MUTYH is an important DNA glycosylase that prevents mutations by initiating base-excision repair at OG:A mismatches. The enzyme activity significantly relies on two metal cofactors: a [4Fe-4S] cluster and a Zn linchpin. Cancer-associated variants near the [4Fe-4S] cofactor revealed that most variants cause disruptions to the enzyme's functions. Furthermore, Arg241 and Asn238 build a structural bridge connecting the [4Fe-4S] cluster to the catalytic Asp236 which is positioned for base excision. Structural and computational analysis of the wild-type, R241Q, and N238S mutant systems of human and mouse enzymes, demonstrate that these mutations impact both the structural dynamics and the interconnections among the residues in the structural bridge.