Inhibition of the DNA damage response by deubiquitinating enzymes

2010 Fiscal Year Final Research Report

• Project/Area Number: 21870033
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Molecular biology
• Research Institution: Keio University
• Principal Investigator: NAKADA Shinichiro Keio University, 医学部, 講師 (70548528)
• Project Period (FY): 2009 – 2010
• Keywords: DNA損傷応答 / ユビキチン / ヒストン / 脱ユビキチン化酵素

Research Abstract

I reported that OTUB1, a deubiquitinating enzyme, was an inhibitor of DSB-induced chromatin ubiquitination. Surprisingly, we found that OTUB1 suppressed RNF168-dependent poly-ubiquitination independently of its catalytic activity. OTUB1 did so by binding to and inhibiting UBC13, the cognate E2 enzyme for RNF168. This unusual mode of regulation was unlikely to be limited to UBC13 because analysis of OTUB1-associated proteins revealed that OTUB1 bound to E2s of the UBE2D and UBE2E subfamilies. Finally, OTUB1 depletion mitigated the DSB repair defect associated with defective ATM signalling, indicating that pharmacological targeting of the OTUB1-UBC13 interaction might enhance the DNA damage response.

Research Products

• [Journal Article] D. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. (2010)
  • Author(s): Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang YC, O'Donnell L, Kumakubo A, Munro M, Sicheri F, Gingras AC, Natsume T, Suda T, Durocher
  • Journal Title: Nature. 466(7309) Pages: 941-6
  • Peer Reviewed
• [Presentation] DNA double strand break and chromatin ubiquitination. (2011)
  • Author(s): 中田慎一郎
  • Organizer: 第115回小児血液腫瘍懇話会
  • Place of Presentation: 東京
  • Year and Date: 2011-01-21
• [Presentation] Durocher D. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. EMBO workshop. (2010)
  • Author(s): Nakada S
  • Organizer: The interface between the ubiquitin family and the DNA damage response.
  • Place of Presentation: Rovinj, Croatia
  • Year and Date: 20100901-20100905
• [Presentation] OTUB1によるATM 依存性DNA損傷応答の調節 (招聘) (2010)
  • Author(s): 中田慎一郎
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会 ワークショップ:2W18 ATMファミリータンパク質をターゲットとしたDNA損傷応答研究の新たなる展開
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-08
• [Presentation] Durocher D.OTUB1 sequesters UBC13 and inhibits DNA-damage dependent ubiquitination. (2010)
  • Author(s): Nakada S
  • Organizer: 3R meeting
  • Place of Presentation: Toyama, Japan
  • Year and Date: 2010-10-27
• [Presentation] 脱ユビキチン化酵素OTUB1によるDNA損傷依存性クロマチンユビキチン化の制御 (招聘、英語発表) (2010)
  • Author(s): 中田慎一郎
  • Organizer: 日本放射線影響学会 第53回大会 シンポジウム5 DNA damage response and disease
  • Place of Presentation: 京都
  • Year and Date: 2010-10-21
• [Presentation] 脱ユビキチン化酵素OTUB1による脱ユビキチン活性非依存的DNA 損傷応答抑制 (招聘) (2010)
  • Author(s): 中田慎一郎
  • Organizer: 第69回日本癌学会学術総会シンポジウム:15.DNA修復応答とゲノム不安定性
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Remarks] ホームページ等
  • URL: http://www.careerpath-prj.keio.ac.jp/kanrinmaru/scholar/nakada/index.html