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
Year: 2024
Type: article
Abstract: 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.
Authors: Trasviña-Arenas, Carlos H., Dissanayake, Upeksha C., Tamayo, Nikole, Hashemian, Mohammad, Lin, Wen-Jen, Demir, Merve, Hoyos-Gonzalez, Nallely, Fisher, Andrew J., Cisneros, G. Andrés, Horvath, Martin P., David, Sheila S.
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6911346266