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.  Bacterial and mammalian MutY glycosylases prevents mutations by excising adenine from OG:A mismatches as the first step in base excision repair. Inherited variations of the human MutY homolog, MUTYH are correlated with colorectal polyposis and colorectal cancer, referred to as MUTYH-associated polyposis (MAP).  Our research laboratory provided support for the discovery of MAP by providing functional analysis of the two most common variants in MUTYH revealing a hampered ability to recognize OG.  We have continued to develop a multi-pronged approach using enzymology, cellular repair assays and biophysical studies to reveal functional features of MUTYH variants and the origin of potential defects. Recently, we have focused on MAP variants localized within regions near the [4Fe-4S]<sup>2+</sup> cluster cofactor and in the interdomain connector (IDC) region that connects the catalytic adenine excision domain and the OG recognition domain.  Inspection of MAP variants in the IDC led to the identification of a “zinc linchpin” motif in MUTYH.  Indeed, coordination of Zn(II) within the IDC of MUTYH is required for efficient damage recognition and repair.  We suggest that the presence of this additional metal site in MUTYH enzymes may provide a means to regulate the activity and interactions with protein partners under conditions of high oxidative stress. <br/> <br/>

DNA repair glycosylase MUTYH: From Fe-S clusters to MAP

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.