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Analysis of DNA repair functions of xeroderma pigmentosum gene

Research Project

Project/Area Number 06404077
Research Category

Grant-in-Aid for General Scientific Research (A)

Allocation TypeSingle-year Grants
Research Field Human genetics
Research InstitutionOsaka University

Principal Investigator

TANAKA Kiyoji  Institute for Molecular and Cellular Biology, Osaka University, Division of Cellular Genetics, Professor, 細胞生体工学センター, 教授 (80144450)

Co-Investigator(Kenkyū-buntansha) SAIJO Masafumi  Institute for Molecular and Cellular Biology, Osaka University, Division of Cell, 細胞生体工学センター, 助手 (90221986)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥21,000,000 (Direct Cost: ¥21,000,000)
Fiscal Year 1995: ¥8,100,000 (Direct Cost: ¥8,100,000)
Fiscal Year 1994: ¥12,900,000 (Direct Cost: ¥12,900,000)
KeywordsDNA repair / xeroderma pigmentosum / DNA binding / Zn-finger / gene targeting / knock-out mouse / carcinogenesis / p53 gene / DNA結合ドメイン / 紫外線
Research Abstract

XPA gene is a causative gene for human genetic disease, xeroderma pigmentosum group A (XPA) and one of the important genes responsible for nucleotide excision repair (NER) in man and encodes a protein of 273 amino acids. We found that the XPA gene product (XPA protein) preferentially bound to the damaged DNA,suggesting its role in damage recognition step of NER.The damaged DNA binding activity is localized in the region encompassed by the MF122 protein (amino acid residues 98 to 219) which is a discretely folded, functional mini-domain, and contains C4 zinc-finger motif. Moreover, the XPA protein has domains to interact with other proteins. Using yeast two hybrid system, we found that the ERCC1 repair protein, replication protein A (RPA) and several other proteins bind to the XPA protein.
The interaction between XPA and ERCC1 or RPA enhanced the damaged DNA binding activity of the XPA protein, suggesting that the interaction may coordinate the damage-recognition step of NER.Yeast homologs of new XPA-binding proteins have been cloned. We are making yeast mutants lacking these genes to see whether they will show a defective NER.
We established XPA-deficient mice using gene targeting technology in ES cells. They are defective in NER and highly susceptible to ultraviolet light-or chemical carcinogen-induced skin carcinogeneis. They also had smaller brain. The XPA-deficient mice may provide a useful tool to study a multistep process of ultraviolet light-induced skin carcinogenesis and a molecular basis of the neurological disturbance in xeroderma pigmentosum patients.

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Kobayashi, T.: "Mutations in the XPD gene leading to xeroderma pigmentosum symptoms" Human Mutation. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Kuraoka, I.: "Identification of a damaged-DNA binding domain of the XPA protein" Mutation Research. 362. 87-95 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsuda, T.: "DNA repair protein XPA binds replication protein A" J.Biolofical Chemistry. 270. 4152-4157 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Nagai, A.: "Enhancement of the damaged DNA binding activity of XPA by interaction with the ERCC1 DNA repair protein" Biochem. Biophys. Res. Comm.211. 960-966 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Nakano, H.: "High incidence of ultraviolet-B-or chemical-carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum group A gene" Nature. 377. 165-168 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Shimamoto, T.: "Expression and functional analyses of Dxpa gene,the Drosophila homolog of a human excision repair gene" J.Biolofical Chemistry. 270. 22452-22459 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Kobayashi, T.: "Mutations in the XPD gene leading to xeroderma pigmentosum symptoms." Human Mutation. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Kuraoka, I.: "Identification of a damaged-DNA binding domain of the XPA protein." Mutation Research. 362. 87-95 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Matsuda, T.: "DNA repair protein XPA binds replication protein A." J.Biological Chemistry. 270. 4152-4157 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Nagai, A.: "Enhancement of the damaged DNA binding activity of XPA by interaction with the ERCC1 DNA repair protein." Biochem.Biophys.Res.Comm.211. 960-966 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Nakane, H.: "High incidence of ultraviolet-B-or chemical-carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum group A gene." Nature. 377. 165-168 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Shimamoto, T.: "Expression and functional analyzes of Dxpa gene, the Drosophila homolog of a human excision repair gene." J.Biological Chemistry. 270. 22452-22459 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Kobayashi,T.: "Mutations in the XPD gene leading to xeroderma pigmentosum symptoms" Human Mutation. (in press).

    • Related Report
      1995 Annual Research Report
  • [Publications] Kuraoka,I.: "Identification of a damaged-DNA binding domain of the XPA protein" Mutation Research. 362. 87-95 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Matsuda,T.: "DNA repair protein XPA binds replication protein A" J. Biological Chemistry. 270. 4152-4157 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nagai,A.: "Enhancement of the damaged DNA binding activity of XPA by interaction with the ERCC1 DNA repair protein" Biochem. Biophys. Res. Comm.211. 960-966 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nakane,H.: "High incidence of UVB- or Chemical carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum" Nature. 377. 165-168 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Shimamoto,T.: "Expression and functional analyses of Dxpa gene, the Drosophila homolog of a human excision repair gene" J. Biological Chemistry. 270. 22452-22459 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Toshiro Matsuda et al.: "DNA repair protein XPA binds replication protein A(RPA)." J.Biol.Chem.270. 4152-4157 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hiroshi Asahina et al.: "The XPA protein is a zinc metalloprotein with an ability to recognize various kinds of DNA damage." Mutation Research. 315. 229-237 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Chikahide Masutani et al.: "Purification and cloning of a nucleotide excision repair complex involving the xeroderma pigmentosum group C protein and a human homologue of yeast RAD23." EMBO.J. 13. 1834-1843 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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