• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

A novel mechanism for preventing mutations caused by oxidation of guanine nucleotides

Research Project

Project/Area Number 14580687
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

TAKAGI Yasumitsu  Fukuoka Dental College, Dep. of Dentistry, Associate Professor, 歯学部, 助教授 (20212003)

Co-Investigator(Kenkyū-buntansha) SEKIGUCHI Mutsuo  Fukuoka Dental College, Institute for, Director, 所長 (00037342)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsDNA repair / DNA oxidation / Spontaneous mutation / oxidation of guanine nucleotides / Spontaneous carcinogenesis
Research Abstract

MutT-related proteins degrade 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP), a mutagenic substrate for DNA synthesis, in the nucleotide pool, thereby preventing DNA replication errors. During a search of GenBank EST database, we found a new member of MutT-related protein, MTH2, which possesses the 23-amino acid MutT module. The cloned mouse MTH2 (mMTH2) cDNA was expressed in Escherichia coli mutT(-) cells and the protein was purified. mMTH2 protein hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, with Km of 32&mgr;M. Expression of cDNA for mMTH2 reduced significantly the elevated level of spontaneous mutation frequency of E. coli mutT(-) cells. Thus, MTH2 has a potential to protect the genetic material from the untoward effects of endogenous oxygen radicals. MTH2 could act as an MTH1 redundancy factor.
Also, we reported that human cells have another mechanism for cleaning up the nucleotide pool to ensure accurate DNA replication. The human Nudix type 5 (NUDT5) protein hydrolyses 8-oxo-dGDP to monophosphate with a K(m) of 0.77 microM, a value considerably lower than that for ADP sugars, which were originally identified as being substrates of NUDT5. NUDT5 hydrolyses 8-oxo-dGTP only at very low levels, but is able to substitute for MutT when it is defective. When NUDT5 is expressed in E. coli mutT(-) cells, the increased frequency of spontaneous mutations is decreased to normal levels. Considering the enzymatic parameters of MTH1 and NUDT5 for oxidized guanine nucleotides, NUDT5 might have a much greater role than MTH1 in preventing the occurrence of mutations that are caused by the misincorporation of 8-oxoguanine in human cells.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Sanada, M., Takagi, Y., Ito, R., Sekiguchi, M.: "Killing and mutagenic actions of dacarbazine, a chemotherapuetic alkylating agent, on human and mouse cells : effects of Mgmt and Mlh1 mutations."DNA repair. 3. 413 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takagi, Y., et al.: "Roles of MGMT and MLH1 proteins in alkylation-induced apoptosis and mutagenesis."DNA repair. 2. 1135 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Cai, J.P., Ishibashi, T., Takagi, Y., Hayakawa, H., Sekiguchi, M.: "Mouse MTH2 protein which prevents mutations caused by 8-oxoguanine nucleotides."Biochem Biophys Res Commun. 305. 1073 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ishibashi, T., Sekiguchi, M.: "A novel mechanism for preventing mutations caused by oxidation of guanine nucleotides"EMBO Repport. 4. 479 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sanada, M., Takagi, Y., Ito, R., Sekiguchi, M.: "Killing and mutagenic actions of dacarbazine, a chemotherapeutic alkylating agent, on human and mouse cells : effects of Mgmt and Mlh1 mutations."DNA Repair. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takagi, Y., Takahashi, M., Sanada, M., Ito, R., Yamaizumi, M., Sekiguchi, M.: "Roles of MGMT and MLH1 proteins in alkylation-induced apoptosis and mutagenesis."DNA Repair. 2. 1135-1146 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Cai, J., Ishibashi, T., Takagi, Y., Hayakawa, H., Sekiguchi, M.: "Mouse MTH2 protein which prevents mutations caused by 8-oxoguanine nucleotides."Biochem Biophys Res Commun. 305. 1073-1077 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ishibashi, T., Sekiguchi, M.: "A novel mechanism for preventing mutations caused by oxidation of guanine nucleotides."EMBO Report. 4. 479-481 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sanada, M., Takagi, Y., Ito, R., Sekiguchi, M.: "Killing and mutagenic actions of dacarbazine, a chemotherapuetic alkylating agent, on human and mouse cells : effects of Mgmt and Mlh1 mutations."DNA repair. In press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takagi, Y., et al.: "Roles of MCMT and MLH1 proteins in alkylation-induced apoptosis and mutagenesis"DNA repair. 2. 1135 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Cai, J.P., Ishibashi, T., Takagi, Y., Hayakawa, H., Sekiguchi, M.: "Mouse MTH2 protein which prevents mutations caused by 8-oxoguanine nucleotide"Biochem Biophys Res Commun. 305. 1073 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ishibashi, T., Sekiguchi, M.: "A novel mechanism for preventing mutations caused by oxidation of guanine nucleotides"EMBO Report. 4. 479 (2003)

    • Related Report
      2003 Annual Research Report

URL: 

Published: 2002-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi