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

Carlos H. Trasviña-Arenas, Upeksha C. Dissanayake, Nikole Tamayo, Mohammad Hashemian, Wen-Jen Lin, Merve Demir, Nallely Hoyos-Gonzalez, Andrew J. Fisher, G. Andrés Cisneros (), Martin P. Horvath () and Sheila S. David ()
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Carlos H. Trasviña-Arenas: University of California
Upeksha C. Dissanayake: University of Texas at Dallas
Nikole Tamayo: University of California
Mohammad Hashemian: University of California
Wen-Jen Lin: University of California
Merve Demir: University of California
Nallely Hoyos-Gonzalez: University of California
Andrew J. Fisher: University of California
G. Andrés Cisneros: University of Texas at Dallas
Martin P. Horvath: University of Utah
Sheila S. David: University of California

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract MUTYH is a clinically important DNA glycosylase that thwarts mutations by initiating base-excision repair at 8-oxoguanine (OG):A lesions. The roles for its [4Fe-4S] cofactor in DNA repair remain enigmatic. Functional profiling of cancer-associated variants near the [4Fe-4S] cofactor reveals that most variations abrogate both retention of the cofactor and enzyme activity. Surprisingly, R241Q and N238S retained the metal cluster and bound substrate DNA tightly, but were completely inactive. We determine the crystal structure of human MUTYH bound to a transition state mimic and this shows that Arg241 and Asn238 build an H-bond network connecting the [4Fe-4S] cluster to the catalytic Asp236 that mediates base excision. The structure of the bacterial MutY variant R149Q, along with molecular dynamics simulations of the human enzyme, support a model in which the cofactor functions to position and activate the catalytic Asp. These results suggest that allosteric cross-talk between the DNA binding [4Fe-4S] cofactor and the base excision site of MUTYH regulate its DNA repair function.

Date: 2025
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DOI: 10.1038/s41467-025-58361-w

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