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Mechanism for control of mutagenesis in mammals

Research Project

Project/Area Number 09440255
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 遺伝
Research InstitutionFukuoka Dental College

Principal Investigator

SEKIGUCHI Mutsuo  Fukuoka Dental College, Department of Biology, Professor, 歯学部, 教授 (00037342)

Co-Investigator(Kenkyū-buntansha) ITO Riyoko  Fukuoka Dental College, Department of Biology, Research associate, 歯学部, 助手 (10140865)
SHIMOKAWA Hidetoshi  Fukuoka Dental College, Department of Biology, Research associate, 歯学部, 助手 (50122792)
SANADA Masayuki  Fukuoka Dental College, Department of Biology, Lecturer, 歯学部, 講師 (40084264)
作見 邦彦  九州大学, 生体防御医学研究所, 助手 (50211933)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 1998: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 1997: ¥8,500,000 (Direct Cost: ¥8,500,000)
KeywordsReactive oxygen / spontaneous mutation / mutation rate / 8-oxoguanine / DNA precursor / DNA replication / replication error / MTH1 gene / 遺伝子障害 / 酸化塩基 / 突然変異 / 変異タンパク / DNA修復 / 遺伝子 / 塩基置換
Research Abstract

Reactive oxygen species produced during normal cellular matabolism damage DNA and its precursors. An oxidized form of guanine base, 8-oxoguanine, is regarded as most critical in terms of mutagenesis as well as carcinogenesis. An enzyme 8-oxo-dGTPase hydrolyzes 8-oxo-dGTP, an oxidized form of dGTP, to 8-oxo-dGMP, thereby preventing the occurrence of A : T to C : G transversion, caused by rnisincorporation of 8-oxo-dGTP into DNA.
To elucidate the role of 8-oxo-dGTPase in carcinogenesis, it is necessary to construct cell or mouse lines with altered levels of the enzyme activity. We isolated the genomic sequence for mouse 8-oxo-dGTPase protein, identified the exon / intron region of the gene MTH1, and characterized the promoter in relation to the regulation of expression of the gene. Based on these data, we performed an gene targeting experiment using ES cells. The ES cells defective in both alleles of the MTH1 gene are viable but yield a moderately higher frequency of spontaneous mutation. By sing MTH1-defective ES cells, we constructed mouse lines defective in both alleles of the MTH1 gene. The mice are viable and apparently normal in appearance but produced a significantly large number of tumores in their organs, especially in stomach.
The mouse MTH1 gene has 5 exons, among which the coding sequence resides on the third through the fifth exon, and spans approximately 9 kb. Part of the human and rat genes for 8-oxo-dGTPase has been isolated, and the human gene is composed of five exons while the rat gene has three exons. A comparison of the gross structures of the genes revealed that the overall structures of the human and rat genes are similar to that of the mouse gene.

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] H.Igarashi: "Organization and expression of the mouse MTH1 gene for preventing transversion mutation." J.Biol.Chem.272. 3766-3772 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] P.J.Cai: "Significance of the conserved amino acid sequence for human MTH1 protein with antimutator activity." Nucl.Acids Res.25. 1170-1176 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Tominaga: "Alkylation-indued apoptosis of embryonic stem cells in which the gene for DNA-repair methy 1 transferase been disrupted by gene targeting." Carcinogenesis. 18. 889-896 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Sakumi: "Methylnitrosourea-induced tumorigenesis in MGMT gene-knokout mice." Cancer Res.57. 2415-2418 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Iwakuma: "High incidence of nitrosamine-induced tumorigenesis in mice lacking DNA repair methyltransferase." Carcinogenesis. 180. 1631-1635 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] D.W.Porter: "Sensitivity of Escherichia coli(MutT)and human (MTH1)8-oxo-dGTPase to in vitro inhibition by carcinogenic metals ; nickle(II), Cobalt(II), and cadmium(II)." Carcinogenesis. 18. 1785-1791 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kawate, H., Sakumi, K., Tsuzuki, T., Nakatsuru, T., Ishikawa, T., Takahashi, S., Takano, H., Noda, T.and Sekiguchi, M.: "Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes." Proc.Natl.Acad.Sci.USA. 95. 5116-5512 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kobayashi, M., Ohara-Nemoto, Y., Kaneko, M., Hayakawa, H., Sekiguchi, M.and Yamamoto, K.: "Potential of Escherichia coli GTP cyclohydolase for hydrolyzing 8-oxo-dGTP,a mutagenic substrate for DNA synthesis." J.Biol.Chem.273. 26394-26399 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohtsubo, T., Matsuda, O., Iba, K., Terashima, I., Sekiguchi, M.and Nakabeppu, Y.: "Molecular cloning of AtMMH,an Arabidopsis thaliana ortholog of the Escherichia coli mutM gene, and analysis of functional domains of its product." Mol.Gen.Genet.259. 577-590 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hayakawa, H., Hofer, A., Thelander, L., Kitajima, S., Cai, Y., Oshiro, S., Yakushiji, H., Nakabeppu, Y., Kuwano, M.and Sekiguchi, M.: "Metabolic fate of oxidized guanine ribonucleotides in mammalian cells." Biochemistry. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kang, D., Takeshige, K., Sekiguchi, M.and Sigh, K.: "Introduction to mitochondrial DNA mutations." Mitochondrial DNA Mutations in Aging, Disease and Cancer. 1-15 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] H.Kawate: "Separation of killing and tumorigenic effects of an alkylating agnet in mice defective in two of DNA repair genes" Proc.Natl.Acad.Sci.U.S.A.95. 5116-5120 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] M.Kobayashi: "Potential of Escherichia coli GTP cyclohydrolase for hydrolyzing 8-oxo-dGTP,a mutagenic substrate for DNA synthesis." J.Biol.Chem.273. 26394-26399 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Otsubo: "Molecular cloning AtMMH,an Arabidopsis thabiara ortholog of the Escherichia coli mutM gene,and analysis of functional domain of itsproduct." Mol.Gen.Genet.259. 577-590 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Hayakawa: "Metabolic fate of oxidized guanine ribonucleotides in mammalian cells." Biochemistry. in press. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.yakushiji: "Biochemical and physicochemical characterization of normal and variant forms of human MTH1 protein with antimugagenic activity." Mutat.Res.,. 384. 181-194 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] F.Taddei: "Counteraction by MutT protein of transcriptional errors caused by oxidative damage." Science. 278. 128-130 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Oda: "Regulation of expression of the human MTH1 gene encoding 8-oxo-dGTPase:Alternative splicing of transcription products." J.Biol.Chem.272. 17843-17850 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Kawate: "Separation of killing and tumorigenic effects of an alkylating agnet in mice defective in two of DNA repair genes" Proc.Natl.Acad.Sci.U.S.A.95. 5116-5120 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] M.Kobayashi: "Potential of Escherichia coli GTP cyclohydrolase for hydrolyzing 8-oxo-dGTP,a mutagenic substrate for DNA synthesis." J.Biol.Chem.273. 26394-26399 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Otsubo: "Molecular cloning AtMMH,an Arabidopsis thabiara ortholog of the Escherichia coli mutM gene,and analysis of functional domain of itsproduct." Mol.Gen.Genet.259. 577-590 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Hayakawa: "Metabolic fate of oxidized guanine ribonucleotides in mammalian cells." Biochemistry. in press. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] K.K.Singh: "Mitochondrial DNA mutations in aging,disease and cancer" Landes Bioscience, 255 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 関口 睦夫: "遺伝子工学" 朝倉書店, 225 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Igarashi et al.: "Organization and expression of the mouse MTH1 gene for preventing transversion mutation" J.Biol.Chem.272. 3766-3772 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] J.-P.Cai et al.: "Significance of the conserved amino acid sequence for human MTH1 protein with antimutator activity" Nucleic Acids Res.25. 1170-1176 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Yakushiji et al.: "Biochemical and physicochemical characteritation of normal and variant forms of human MTH1 protein with antimutagenic activity" Mutation Res.384. 181-194 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] D.W.Porter et al.: "Sensitivity of E.coli(Mut T)and human(MTH1)8-oxo-dGTPase to in vitro inhibition by carcinogenic metals" Carcinogenesis. 18. 1785-1791 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] F.Taddai et al.: "Transcriptional errors caused by oxidative damage are counteracted by MutT protein" Science. 278. 128-130 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Oda et al.: "Regulation of expression of the human MTH1 gene encoding 8-oxo-dGTPase:Alternative splicing of transcription products" J.Biol.Chem.272. 17843-17850 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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