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DNA replication and post replication DNA repair affect the genomic instability and cancer suppression

Research Project

Project/Area Number 16590244
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionNagoya University

Principal Investigator

SUZUKI Motoshi  Nagoya University, Graduate School of Medicine, Assistant Professor, 大学院・医学系研究科, 講師 (80236017)

Co-Investigator(Kenkyū-buntansha) MURATE Takashi  Nagoya University, School of Medicine, Professor, 医学部, 教授 (30239537)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsDNA polymerase / DNA replication / mismatch repair / genomic instability / translesion synthesis / DNA damage / DNA修復 / ユビキチン / チェックポイント / ゲノム統合性
Research Abstract

In order to study how cells establish fidelity DNA replication during the lagging strand DNA replication, we isolated active mutants in Saccharomyces cerevisiae pol alpha that have a defect in error discrimination. Among them, L868F pol alpha has a spontaneous error frequency of 3 in 100 nucleotides and 570-fold lower replication fidelity than wild type. In vivo, L868F pol alpha confers a mutator phenotype. For this result, we suggest accurate DNA synthesis by pol alpha is important to suppress genomic instability in cells. We also found L868F pol alpha catalyzed relatively efficient bypass of a cis-syn cyclobutane pyrimidine dimer, extending the 3'-T 26000-fold more efficiently than wild type. This type of activity is characteristic to translesion DNA polymerases, which are classified in another family of DNA polymerases. Interestingly, leucine and phenylalanine residues are conserved in replicative and translesion DNA polymerases, respectively. In a translesion DNA polymerase eta mutant of S. cerevisiae F34L pol eta showed reduced translesion DNA synthesis activity in vitro. The corresponding mutants in human DNA polymerases also showed the similar biochemical features. These data suggest that the phenylalanine and leucine residues may have played a role in the functional evolution of these enzyme classes.
The observed high fidelity of chromosomal replication is achieved not only through mechanisms that enhance correct nucleotide insertion by the DNA polymerase but also through ones that correct errors after they occur. We are under investigation of the downstream pathways that may either suppress or promote genomic instability.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (15 results)

All 2005 2004 Other

All Journal Article (15 results)

  • [Journal Article] Transcription factor Spl is the main regulator of NGF-induced sphingosine kinase I gene expression of the rat pheochromocytoma cell line, PC12.2005

    • Author(s)
      Sobue, S.
    • Journal Title

      J Neurochem 95・4

      Pages: 940-949

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] ゲノム安定化におけるDNAポリメラーゼαの役割2005

    • Author(s)
      新美敦子
    • Journal Title

      生化学 77・3

      Pages: 200-205

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Transcription factor Sp1 is the main regulator of NGF-induced sphingosine kinase 1 gene expression of the rat pheochromocytoma cell line, PC12.2005

    • Author(s)
      Sobue, S.
    • Journal Title

      J Neurochem 95-4

      Pages: 940-949

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Function of DNA polymerase alpha on genomic stability.2005

    • Author(s)
      Niimi, A.
    • Journal Title

      Seikagaku 77-3

      Pages: 200-205

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Transcription factor Sp1 is the main regulator of NGF-induced sphingosine kinase 1 gene expression of the rat pheochromocytoma cell line, PC12.2005

    • Author(s)
      Sobue, S.
    • Journal Title

      J Neurochem 95・4

      Pages: 940-949

    • Related Report
      2005 Annual Research Report
  • [Journal Article] ゲノム安定化におけるDNAポリメラーゼαの役割2005

    • Author(s)
      新美 敦子 他
    • Journal Title

      生化学 (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Palm Mutants in DNA polymerases alpha and eta Alter DNA Replication Fidelity and Transesion Activity.2004

    • Author(s)
      Niimi, A.
    • Journal Title

      Mol Cell Biol 24・7

      Pages: 2734-2746

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The alpha4 residues of human DNA topoisomerase IIalpha function in enzymatic activity and anticancer drug sensitivity.2004

    • Author(s)
      Suda, N.
    • Journal Title

      Nucleic Acids Res 32・5

      Pages: 1767-1773

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Palm Mutants in DNA Polymerases alpha and eta Alter DNA Replication Fidelity and Translesion Activity.2004

    • Author(s)
      Niimi, A.
    • Journal Title

      Mol Cell Biol 24-7

      Pages: 2734-2746

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The alpha4 residues of human DNA topoisomerase IIalpha function in enzymatic activity and anticancer drug sensitivity.2004

    • Author(s)
      Suda, N.
    • Journal Title

      Nucleic Acids Res 32-5

      Pages: 1767-1773

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Palm Residue Mutants in DNA Polymerases・and・Alter DNA Replication Fidelity and Translesion Activity2004

    • Author(s)
      Niimi A., et al.
    • Journal Title

      Molecular and Cellular Biology 24・7

      Pages: 2734-2746

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The alpha4 residues of human DNA topoisomerase IIalpha function in enzymatic activity and anticancer drug sensitivity.2004

    • Author(s)
      Suda N., et al.
    • Journal Title

      Nucleic Acids Resarch 32・5

      Pages: 1767-1773

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Exonucleolytic Correction in Trans of Eukaryotic Lagging Strand DNA Replication Errors

    • Author(s)
      Pavlov, Y.I.
    • Journal Title

      Curr Biol (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Exonucleolytic Correction in Trans of Eukaryotic Lagging Strand DNA Replication Errors

    • Author(s)
      Pavlov, Y.I.
    • Journal Title

      Curr Biol (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Exonucleolytic Correction in Trans of Eukaryotic Lagging Strand DNA Replication Errors

    • Author(s)
      Pavlov, Y.I.
    • Journal Title

      Curr Biol (In press)

    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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