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

30 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

Fingerprint

DNA Glycosylases
Human Activities
Colorectal Neoplasms
Proteins
Adenine
DNA Repair
adenine glycosylase
Germ-Line Mutation
Guanine
Recombinant Proteins
Adenoma

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Adenine DNA glycosylase activity of 14 Human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer. / Goto, Masanori; Shinmura, Kazuya; Nakabeppu, Yusaku; Tao, Hong; Yamada, Hidetaka; Tsuneyoshi, Toshihiro; Sugimura, Haruhiko.

In: Human mutation, Vol. 31, No. 11, 01.11.2010, p. E1861-1874.

Research output: Contribution to journalArticle

Goto, Masanori ; Shinmura, Kazuya ; Nakabeppu, Yusaku ; Tao, Hong ; Yamada, Hidetaka ; Tsuneyoshi, Toshihiro ; Sugimura, Haruhiko. / Adenine DNA glycosylase activity of 14 Human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer. In: Human mutation. 2010 ; Vol. 31, No. 11. pp. E1861-1874.
@article{c23823daa3aa4e89be0cbf5bcb9d35ef,
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.",
author = "Masanori Goto and Kazuya Shinmura and Yusaku Nakabeppu and Hong Tao and Hidetaka Yamada and Toshihiro Tsuneyoshi and Haruhiko Sugimura",
year = "2010",
month = "11",
day = "1",
doi = "10.1002/humu.21363",
language = "English",
volume = "31",
pages = "E1861--1874",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "11",

}

TY - JOUR

T1 - Adenine DNA glycosylase activity of 14 Human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer

AU - Goto, Masanori

AU - Shinmura, Kazuya

AU - Nakabeppu, Yusaku

AU - Tao, Hong

AU - Yamada, Hidetaka

AU - Tsuneyoshi, Toshihiro

AU - Sugimura, Haruhiko

PY - 2010/11/1

Y1 - 2010/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=78049418933&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78049418933&partnerID=8YFLogxK

U2 - 10.1002/humu.21363

DO - 10.1002/humu.21363

M3 - Article

VL - 31

SP - E1861-1874

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 11

ER -