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Study on the role for HERC2 in the response to replication stress

Research Project

Project/Area Number 17K08676
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pathological medical chemistry
Research InstitutionSt. Marianna University School of Medicine

Principal Investigator

Wu Wenwen  聖マリアンナ医科大学, 医学研究科, 准教授 (10434408)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsHERC2 / BLM / RPA / DNA複製ストレス応答 / グアニン4重鎖 / RPA2 / ユビキチン化 / MCM
Outline of Final Research Achievements

In this study, we found that an HECT E3 ligase HERC2 interacts with RecQ helicases BLM and WRN, and is a master regulator of G4 suppression. HERC2 depletion resulted in elevated level of sister chromatid exchange and in a dramatic G4 accumulation in a manner epistatic to depletion of BLM and WRN. Inactivation of E3 ligase activity of HERC2 by Cas9/CRISPR-mediated gene editing demonstrates an essential role of the activity to prevent the phenotype. Mechanistically, HERC2 regulates the interaction of the helicases with replication protein A (RPA), which is known to support the helicase activity to unfold G4s. In addition, HERC2 regulates ATR-phosphorylated RPA2 levels through induction and degradation. Importantly, the HERC2 dysfunctions sensitize cells to G4 stabilizers telomestatin and pyridostatin. Given that the HERC2 expression is frequently reduced in many types of cancers, the G4 accumulation by HERC2 deficiency may provide a therapeutic target for the G4 stabilizers.

Academic Significance and Societal Importance of the Research Achievements

HERC2あるいはそのE3活性の欠失により、DNAヘリカーゼであるBLMとWRNの機能が損なわれてG4が蓄積し、細胞はG4安定化剤であるピリドスタチンおよびテロメスタチンに対して高い感受性を示した。多くのタイプのがんにおいてHERC2の発現が減少していることから、HERC2の機能不全によるG4の蓄積はがん治療においてG4安定化剤の標的あるいは効果の指標となることが期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (10 results)

All 2019 2018 2017 Other

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (5 results) (of which Int'l Joint Research: 2 results) Remarks (2 results)

  • [Journal Article] HERC2 regulates RPA2 by mediating ATR-induced Ser33 phosphorylation and ubiquitin-dependent degradation.2019

    • Author(s)
      Lai Y, Zhu M, Wu W, Rokutanda N, Togashi Y, Liang W, Ohta T.
    • Journal Title

      Sci Rep.

      Volume: 9 Issue: 1 Pages: 14257-14257

    • DOI

      10.1038/s41598-019-50812-x

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] HERC2 facilitates BLM and WRN helicase complex interaction with RPA to suppress G-quadruplex DNA.2018

    • Author(s)
      Wu W, Rokutanda N, Takeuchi J, Lai Y, Maruyama R, Togashi Y, Nishikawa H, Arai N, Miyoshi Y,Suzuki N, Saeki Y, Tanaka K, Ohta T.
    • Journal Title

      Cancer Res.

      Volume: 78 Issue: 22 Pages: 6371-6385

    • DOI

      10.1158/0008-5472.can-18-1877

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer.2018

    • Author(s)
      Johmura Y, Maeda I, Suzuki N, Wu W, Goda A,Morita M, Yamaguchi K, Yamamoto M, Nagasawa S, Kojima Y, Tsugawa K, Inoue N, Miyoshi Y, Osako T Akiyama F, Maruyama R, Inoue JI, Fukukawa Y, Ohta T, Nkanishi M.
    • Journal Title

      J Clin Invest.

      Volume: 128 Issue: 12 Pages: 5603-5619

    • DOI

      10.1172/jci121679

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] PARP阻害剤耐性獲得に対する治療戦略.2019

    • Author(s)
      太田智彦, 朱明章, 呉文文.
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] HERC2 regulates the status of Ser33-phosphorylated RPA2 through both induction and ubiquitin-dependent degradation.2019

    • Author(s)
      Wu Wenwen.
    • Organizer
      The ubiquitin system: Biology, mechanisms and roles in disease(EMBO Workshop)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] HERC2 ubiquitinates RPA2 in ATR dependent manner and promotes RPA to suppress G-quadruplex DNA.2019

    • Author(s)
      Yongqiang Lai, Mingzhang Zhu, Wenwen Wu, Yukiko Togashi, Tomohiko Ohta.
    • Organizer
      11th AACR-JCA Joint Conference onBreakthroughs in Cancer Research
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] HERC2はグアニン四重鎖(G4)の主要な制御因子としてG4安定化剤の感受性を左右する.2018

    • Author(s)
      呉文文, 竹内淳, 頼勇強, 三好康雄, 鈴木直, 佐伯泰, 田中啓二, 朱明章, 太田智彦.
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Resistance of Fbxo22 knockout cancer cells to poly(ADP-ribose)polymerase(PARP)inhibitor2017

    • Author(s)
      頼勇強, 呉文文, 梁偉新, 太田智彦
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Remarks] 聖マリアンナ医科大学病院 医学研究科 応用分子腫瘍学

    • URL

      http://www.marianna-u.ac.jp/t-oncology/index.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] 聖マリアンナ医科大学大学院 医学研究科 応用分子腫瘍学

    • URL

      http://www.marianna-u.ac.jp/t-oncology/index.html

    • Related Report
      2018 Research-status Report 2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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