Characterization Of A Novel Human Mutyh Variant Causing Colonic Polyposis Through Disruption Of The Fe-S Cluster

e12514 Background: MUTYH is a human DNA repair enzyme functioning to abscise adenine residues mispaired with 8-oxo-7,8-dihydroguanine (8-oxoG) in oxidatively damaged DNA. This repair activity prevents occurrence of G:C to T:A transversions and subsequent carcinogenesis. MUTYH gene mutations underlie the autosomal, recessive cancer syndrome MUTYH-Associated Polyposis (MAP). MUTYH variants are common, and their interpretation and functional assessment inform patient management. Presently, we report a novel MUTYH variant, c.918C u003e G (p.C306W), occurring within the protein’s Fe-S cluster region. Functional analysis of the MUTYH Fe-S cluster has not previously been reported. We provide a functional assessment of the c.918C u003e G MUTYH variant relative to wild type and two well-known MUTYH mutants. Methods: Highly pure wild type, mutant and variant p.C306W MUTYH proteins were prepared with fast protein liquid chromatography (FPLC). Adenine abscission and binding activities were assessed employing capillary electr...