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

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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)881-893
Number of pages13
JournalDNA Repair
Volume1
Issue number11
DOIs
Publication statusPublished - Nov 1 2002

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Mutagenesis
Nucleotides
Genes
Repair
Escherichia coli
DNA
Substrates
Liver
DNA Mismatch Repair
Hydrolysis
Reactive Oxygen Species
Aging of materials
Defects
Mutation
Proteins
Liver Neoplasms
Reporter Genes
Stomach Neoplasms
Lung Neoplasms
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Egashira, A., Yamauchi, K., Yoshiyama, K., Kawate, H., Katsuki, M., Sekiguchi, M., ... Tsuzuki, T. (2002). Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes. DNA Repair, 1(11), 881-893. https://doi.org/10.1016/S1568-7864(02)00113-1

Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes. / Egashira, Akinori; Yamauchi, Kazumi; Yoshiyama, Kaoru; Kawate, Hisaya; Katsuki, Motoya; Sekiguchi, Mutsuo; Sugimachi, Keizo; Maki, Hisaji; Tsuzuki, Teruhisa.

In: DNA Repair, Vol. 1, No. 11, 01.11.2002, p. 881-893.

Research output: Contribution to journalArticle

Egashira, A, Yamauchi, K, Yoshiyama, K, Kawate, H, Katsuki, M, Sekiguchi, M, Sugimachi, K, Maki, H & Tsuzuki, T 2002, 'Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes', DNA Repair, vol. 1, no. 11, pp. 881-893. https://doi.org/10.1016/S1568-7864(02)00113-1
Egashira A, Yamauchi K, Yoshiyama K, Kawate H, Katsuki M, Sekiguchi M et al. Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes. DNA Repair. 2002 Nov 1;1(11):881-893. https://doi.org/10.1016/S1568-7864(02)00113-1
Egashira, Akinori ; Yamauchi, Kazumi ; Yoshiyama, Kaoru ; Kawate, Hisaya ; Katsuki, Motoya ; Sekiguchi, Mutsuo ; Sugimachi, Keizo ; Maki, Hisaji ; Tsuzuki, Teruhisa. / Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes. In: DNA Repair. 2002 ; Vol. 1, No. 11. pp. 881-893.
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AU - Katsuki, Motoya

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