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• W2891643654 endingPage "13271" @default.
• W2891643654 startingPage "13260" @default.
• W2891643654 abstract "The DNA base excision repair (BER) glycosylase MUTYH prevents DNA mutations by catalyzing adenine (A) excision from inappropriately formed 8-oxoguanine (8-oxoG):A mismatches. The importance of this mutation suppression activity in tumor suppressor genes is underscored by the association of inherited variants of MUTYH with colorectal polyposis in a hereditary colorectal cancer syndrome known as MUTYH-associated polyposis, or MAP. Many of the MAP variants encompass amino acid changes that occur at positions surrounding the two-metal cofactor-binding sites of MUTYH. One of these cofactors, found in nearly all MUTYH orthologs, is a [4Fe–4S]2+ cluster coordinated by four Cys residues located in the N-terminal catalytic domain. We recently uncovered a second functionally relevant metal cofactor site present only in higher eukaryotic MUTYH orthologs: a Zn2+ ion coordinated by three Cys residues located within the extended interdomain connector (IDC) region of MUTYH that connects the N-terminal adenine excision and C-terminal 8-oxoG recognition domains. In this work, we identified a candidate for the fourth Zn2+ coordinating ligand using a combination of bioinformatics and computational modeling. In addition, using in vitro enzyme activity assays, fluorescence polarization DNA binding assays, circular dichroism spectroscopy, and cell-based rifampicin resistance assays, the functional impact of reduced Zn2+ chelation was evaluated. Taken together, these results illustrate the critical role that the “Zn2+ linchpin motif” plays in MUTYH repair activity by providing for proper engagement of the functional domains on the 8-oxoG:A mismatch required for base excision catalysis. The functional importance of the Zn2+ linchpin also suggests that adjacent MAP variants or exposure to environmental chemicals may compromise Zn2+ coordination, and ability of MUTYH to prevent disease." @default.
• W2891643654 created "2018-09-27" @default.
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• W2891643654 date "2018-09-12" @default.
• W2891643654 modified "2023-10-14" @default.
• W2891643654 title "The Zinc Linchpin Motif in the DNA Repair Glycosylase MUTYH: Identifying the Zn²⁺ Ligands and Roles in Damage Recognition and Repair" @default.
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• W2891643654 doi "https://doi.org/10.1021/jacs.8b06923" @default.
• W2891643654 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6443246" @default.
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• W2891643654 hasPublicationYear "2018" @default.
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