Inhibition of the DNA damage response by deubiquitinating enzymes

去泛素化酶抑制 DNA 损伤反应

• 批准号: 21870033
• 负责人: NAKADA Shinichiro
• 金额: $ 1.76万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Research Activity Start-up
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21870033/
• 关键词: DNA損傷応答; ユビキチン; ヒストン; 脱ユビキチン化酵素; DNA損傷; クロマチン; コビキチン化; UBC13; OTUB1

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.

我报道OTUB 1是一种去泛素化酶，是DSB诱导的染色质泛素化的抑制剂。令人惊讶的是，我们发现OTUB 1抑制RNF 168依赖的多聚泛素化独立于其催化活性。OTUB 1通过结合并抑制RNF 168的同源E2酶UBC 13来实现。这种不寻常的调控模式不太可能仅限于UBC 13，因为OTUB 1相关蛋白的分析显示OTUB 1与UBE 2D和UBE 2 E亚家族的E2结合。最后，OTUB 1耗竭减轻了与ATM信号传导缺陷相关的DSB修复缺陷，表明OTUB 1-UBC 13相互作用的药理学靶向可能增强DNA损伤反应。

项目成果

Durocher D.OTUB1 sequesters UBC13 and inhibits DNA-damage dependent ubiquitination.

Durocher D.OTUB1 隔离 UBC13 并抑制 DNA 损伤依赖性泛素化。

• 发表时间: 2010
• 作者: Mora;T.;Yu;H.;Sowa;Y. & Wingreen;N.;Nakada S
• 通讯作者: Nakada S

Durocher D. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. EMBO workshop.

Durocher D. OTUB1 对 DNA 损伤依赖性泛素化的非典型抑制。

• 发表时间: 2010
• 作者: Motoki Takaku;Takashi Kainuma;Takako Ishida-Takaku;Shintaro Ishigami;Hidekazu Suzuki;Satoshi Tashiro;Rob W.M.van Soest;Yoichi Nakao;Hitoshi Kurumizaka;Nakada S
• 通讯作者: Nakada S

OTUB1によるATM 依存性DNA損傷応答の調節 (招聘)

OTUB1 调节 ATM 依赖性 DNA 损伤反应（邀请）

• 发表时间: 2010
• 作者: Shinichiro Nakada;et al.;今村壮輔;藤澤誠;佐藤薫;中田慎一郎;藤澤誠;今村壮輔;Kaoru Sato;中田慎一郎
• 通讯作者: 中田慎一郎

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主页等

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)

去泛素化酶 OTUB1 对 DNA 损伤依赖性染色质泛素化的调节（受邀，以英文发表）

• 发表时间: 2010
• 作者: Mora;T.;今村壮輔;曽和義幸;中田慎一郎
• 通讯作者: 中田慎一郎