論文

基本情報

氏名 河手 久弥
氏名(カナ) カワテ ヒサヤ
氏名(英語) HISAYA KAWATE
所属 中村学園大学 栄養科学部 栄養科学科
職名 教授

題名

Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes

単著・共著の別

共著

著者

Akinori Egashira
Kazumi Yamauchi
Kaoru Yoshiyama
Hisaya Kawate
Motoya Katsuki
Mutsuo Sekiguchi
Keizo Sugimachi
Hisaji Maki
Teruhisa Tsuzuki

担当区分

概要

Oxidative damage of nucleotides within DNA or precursor pools caused by oxygen radicals is thought to play an important role in spontaneous mutagenesis, as well as carcinogenesis and aging. In particular, 8-oxodGTP and 2-OHdATP are potent mutagenic substrate for DNA synthesis. Mammalian MTH1 catalyzes hydrolysis of these mutagenic substrates, suggesting that it functions to prevent mutagenesis caused by these oxidized nucleotides. We have established MTH1-/- mice lacking the 8-oxodGTPase activity, which were shown to be susceptible to lung, liver and stomach cancers. To examine in vivo mutation events due to the MTH1-deficiency, a reporter gene, rpsL of Escherichia coli, was introduced into MTH1-/- mice. Interestingly, the net frequency of rpsL- forward mutants showed no apparent increase in MTH1-/- mice as compared to MTH1+/+ mice. However, we found differences between these two genotypes in the class- and site-distributions of the rpsL- mutations recovered from the mice. Unlike MutT-deficient E. coli showing 1000-fold higher frequency of A:T→C:G transversion than the wild type cells, an increase in frequency of A:T→C:G transversion was not evident in MTH1 nullizygous mice. Nevertheless, the frequency of single-base frameshifts at mononucleotide runs was 5.7-fold higher in spleens of MTH1-/- mice than in those of wild type mice. Since the elevated incidence of single-base frameshifts at mononucleotide runs is a hallmark of the defect in MSH2-dependent mismatch repair system, this weak site-specific mutator effect of MTH1-/- mice could be attributed to a partial sequestration of the mismatch repair function that may act to correct mispairs with the oxidized nucleotides. Consistent with this hypothesis, a significant increase in the frequency of G:C→T:A transversions was observed with MTH1-/- MSH2-/- mice over MSH2-/- mice alone. These results suggest a possible involvement of multiple anti-mutagenic pathways, including the MTH1 protein and other repair system(s), in mutagenesis caused by the oxidized nucleotides. © 2002 Elsevier Science B.V. All rights reserved.

発表雑誌等の名称

DNA Repair

出版者

1

11

開始ページ

881

終了ページ

893

発行又は発表の年月

2002/11/01

査読の有無

有り

招待の有無

無し

記述言語

英語

掲載種別

研究論文(学術雑誌)

国際・国内誌

国際共著

ISSN

eISSN

DOI

10.1016/S1568-7864(02)00113-1

Cinii Articles ID

Cinii Books ID

Pubmed ID

PubMed Central 記事ID

形式

無償ダウンロード

JGlobalID

arXiv ID

ORCIDのPut Code

DBLP ID