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Identification and funtional analysis of endonucleases involved in irradiation sensitivity

Research Project

Project/Area Number 25740016
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Risk sciences of radiation and chemicals
Research InstitutionKyoto University

Principal Investigator

MURAI JUNKO  京都大学, 医学(系)研究科(研究院), 助教 (60532603)

Project Period (FY) 2013-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
KeywordsDNA修復 / 抗がん剤 / PARP阻害剤 / トポイソメラーゼ / 薬剤耐性 / がん / 相同組み替え / DNAダメージ / ヌクレアーゼ / 放射線 / 抗がん治療 / DNA損傷 / 併用療法 / PARP
Outline of Final Research Achievements

In this study, we revealed novel function of a DNA repair gene TDP1 (tyrosyl-DNA phosphodiesterase) that is involved in the repair of DNA damages induced by irradiation and chemotherapy. Our findings would lead to a novel strategy to overcome cancers, because the combination of irradiation or chemotherapy in TDP1 deficient cancer cells or TDP1 inhibitors (under development) would augment the cytotoxicity of the treatment.
Furthermore, we have discovered a novel mechanism of action for PARP inhibitors, recently developed anti-cancer agents. Although PARP inhibitors with highly catalytic PARP inhibition tend to be considered equivalent, we found that the potency of the new mechanism of action named “PARP-trapping” is markedly (more than 1,000 folds) different among five clinical PARP inhibitors and that the PARP-trapping potency corresponds to the cytotoxicity of each drug. We also revised the strategy of drug combination with PARP inhibitors based on the new mechanisms.

Report

(3 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • Research Products

    (14 results)

All 2015 2014 2013

All Journal Article (10 results) (of which Peer Reviewed: 9 results,  Open Access: 2 results,  Acknowledgement Compliant: 1 results) Presentation (4 results) (of which Invited: 2 results)

  • [Journal Article] SLFN11 is a transcriptional target of EWS-FLI1 and a determinant of drug response in Ewing's sarcoma2015

    • Author(s)
      Tang, S. W. Bilke, S. Cao, L. Murai, J. Sousa, F. G. Yamade, M. Rajapakse, V. Varma, S. Helman, L. J. Khan, J. Meltzer, P. S. Pommier, Y.
    • Journal Title

      Clin Cancer Res

      Volume: N/A Issue: 18 Pages: 4184-4193

    • DOI

      10.1158/1078-0432.ccr-14-2112

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The POLD3 subunit of DNA polymerase δ can promote translesion synthesis independently of DNA polymerase ζ.2015

    • Author(s)
      Hirota K, Yoshikiyo K, Guilbaud G, Tsurimoto T, Murai J, Tsuda M, Phillips L, Narita T, Nishihara K, Kobayashi K, Yamada K, Nakamura J, Pommier Y, Lehmann, A, Sale J, Takeda S
    • Journal Title

      Nucleic Acids Res.

      Volume: 43 Issue: 3 Pages: 1671-1683

    • DOI

      10.1093/nar/gkv023

    • NAID

      120005825923

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)2014

    • Author(s)
      Pommier, Y. Huang, S. Y. Gao, R. Das, B. B. Murai, J. Marchand, C.
    • Journal Title

      DNA Repair (Amst)

      Volume: 19 Pages: 114-29

    • DOI

      10.1016/j.dnarep.2014.03.020

    • Related Report
      2014 Annual Research Report
  • [Journal Article] Rationale for PARP inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition.2014

    • Author(s)
      Murai J, Zhang Y, Morris J, Ji J, Takeda S, Doroshow J, Pommier YG
    • Journal Title

      J Pharmacol Exp Ther.

      Volume: 349 Issue: 3 Pages: 408-416

    • DOI

      10.1124/jpet.113.210146

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of novel PARP inhibitors using a cell-based TDP1 inhibitory assay in a quantitative high-throughput screening platform.2014

    • Author(s)
      Murai J, Marchand C, Shahane SA, Sun H, Huang R, Zhang Y, Chergui A, Ji J, Doroshow JH, Jadhav A, Takeda S, Xia M, Pommier Y
    • Journal Title

      DNA Repair

      Volume: 21 Pages: 177-182

    • DOI

      10.1016/j.dnarep.2014.03.006

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib.2014

    • Author(s)
      Murai J, Huang SY, Renaud A, Zhang Y, Ji J, Takeda S, Morris J, Teicher B, Doroshow JH, Pommier Y
    • Journal Title

      Mol Cancer Ther.

      Volume: 13 Issue: 2 Pages: 433-443

    • DOI

      10.1158/1535-7163.mct-13-0803

    • Related Report
      2014 Annual Research Report 2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Rationale for PARP inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition.2014

    • Author(s)
      Murai J, Zhang Y, Morris J, Ji J, Takeda S, Doroshow JH, Pommier YG.
    • Journal Title

      Journal of Pharmacology and Experimental Therapeutics

      Volume: ahead of epub

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel.2014

    • Author(s)
      Maede Y, Shimizu H, Fukushima T, Kogame T, Nakamura T, Miki T, Takeda S, Pommier Y, Murai J
    • Journal Title

      Mol Cancer Ther.

      Volume: 13 Issue: 1 Pages: 214-220

    • DOI

      10.1158/1535-7163.mct-13-0551

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] PARP1-TDP1 coupling for the repair of topoisomerase I-induced DNA damage.2014

    • Author(s)
      Das BB, Huang SY, Murai J, Rehman I, Ame JC, Sengupta S, Das SK, Majumdar P, Zhang H, Biard D, Majumder HK, Schreiber V, Pommier Y.
    • Journal Title

      Nucleic Acids Research

      Volume: 42 Issue: 7 Pages: 4435-4449

    • DOI

      10.1093/nar/gku088

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs2013

    • Author(s)
      Shar-yin N. Huang, Junko Murai, Ilaria Dalla Rosa, Thomas S. Dexheimer, Alena Naumova, William H. Gmeiner and Yves Pommier
    • Journal Title

      Nucleic Acids Research

      Volume: 41 Issue: 16 Pages: 7793-7803

    • DOI

      10.1093/nar/gkt483

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] The combination of the PARP inhibitor talazoparib (BMN 673) with the ATR inhibitor VE-821 overcomes the drug resistance of Schlafen 11-deficient cells2015

    • Author(s)
      Junko Murai
    • Organizer
      Association of American Cancer Association 2015
    • Place of Presentation
      Philadelphia, USA
    • Year and Date
      2015-04-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] 新規分子標的がん治療薬PARP阻害剤の作用機序2014

    • Author(s)
      Junko Murai
    • Organizer
      第73回日本癌学会学術総会
    • Place of Presentation
      Pacifico Yokohama
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Mechanism of action of PARP inhibitors, new molecular targeted drugs2014

    • Author(s)
      Junko Murai
    • Organizer
      第47回日本骨軟部腫瘍学会
    • Place of Presentation
      大阪国際会議場
    • Year and Date
      2014-07-18
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Stereospecific trapping of PARP-DNA complexes by BMN 673 and comparison with olaparib and rucaparib2013

    • Author(s)
      Junko Murai
    • Organizer
      AACR-NCI-EORTC 2013
    • Place of Presentation
      Boston
    • Related Report
      2013 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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