DNA repair processes play an important role in maintaining the chemical integrity of DNA and preserving its informational content.  The damaged base 8-oxoguanine (OG) is particularly sinister due to its subtle structural change that evades detection during replication and results in incorrect insertion of adenine to form OG:A mismatches. The bacterial and mammalian MutY glycosylases prevents mutations by excising adenine from OG:A mismatches as the first step in base excision repair.  In addition to an [4Fe-4S] cofactor, we recently identified a new “zinc linchpin” motif in a region of mammalian MutY that connects the catalytic base excision domain and the OG recognition domain.  In vitro and cellular assays on WT and Cys to Ser mutants have revealed an important function for zinc coordination within this region on overall protein stability, iron-sulfur cluster insertion, and ability to mediate DNA damage repair.  We have also found that mammalian MutY enzymes are more sensitive to biological oxidants than their bacterial counterparts due to the presence of this Zinc linchpin motif.  In addition, we have evaluated several human MutY homolog (MUTYH) variants associated with colorectal cancer in this region to determine the influence of these variations on zinc coordination, and DNA repair activity.

Roles for metal cofactors of MutY enzymes in preventing DNA mutations

249th National Meeting (2015)

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