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

• Project/Area Number: 17K08676
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: St. 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: ¥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)
• Keywords: HERC2 / 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。

Research Products

• [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
  • 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
  • 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
  • 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
• [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)
  • 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
  • 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
• [Presentation] Resistance of Fbxo22 knockout cancer cells to poly(ADP-ribose)polymerase(PARP)inhibitor (2017)
  • 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
• [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
• [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