title: Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer.
abstract: Biallelic inactivating germline mutations in the base excision repair MUTYH (MYH) gene have been shown to predispose to MUTYH-associated polyposis (MAP), which is characterized by multiple colorectal adenomas and carcinomas. In this study, we successfully prepared highly homogeneous human MUTYH type 2 recombinant proteins and compared the DNA glycosylase activity of the wild-type protein and fourteen variant-type proteins on adenine mispaired with 8-hydroxyguanine, an oxidized form of guanine. The adenine DNA glycosylase activity of the p.I195V protein, p.G368D protein, p.M255V protein, and p.Y151C protein was 66.9%, 15.2%, 10.7%, and 4.5%, respectively, of that of the wild-type protein, and the glycosylase activity of the p.R154H, p.L360P, p.P377L, p.452delE, p.R69X, and p.Q310X proteins as well as of the p.D208N negative control form was extremely severely impaired. The glycosylase activity of the p.V47E, p.R281C, p.A345V, and p.S487F proteins, on the other hand, was almost the same as that of the wild-type protein. These results should be of great value in accurately diagnosing MAP and in fully understanding the mechanism by which MUTYH repairs DNA in which adenine is mispaired with 8-hydroxyguanine.
authors.affiliation: First Department of Pathology, Hamamatsu University School of Medicine, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Goto
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shinmura
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.forename: Hong
authors.initials: H
authors.lastname: Tao
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamada
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tsuneyoshi
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sugimura
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D011125:Adenomatous Polyposis Coli / Q000201:enzymology* / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism*; D004260:DNA Repair; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D011994:Recombinant Proteins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D003849:Deoxyguanosine