Adenine DNA glycosylase activity of 14 Human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer

Masanori Goto, Kazuya Shinmura, Yusaku Nakabeppu, Hong Tao, Hidetaka Yamada, Toshihiro Tsuneyoshi, Haruhiko Sugimura

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E1861-1874
Number of pages14
JournalHuman mutation
Volume31
Issue number11
DOIs
Publication statusPublished - Nov 1 2010

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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