Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1

被引：306

作者：

Nakada, Shinichiro ^{[2
,3
]}

Tai, Ikue ^{[2
,3
]}

Panier, Stephanie ^{[1
,4
]}

Al-Hakim, Abdallah ^{[1
]}

Iemura, Shun-ichiro ^{[5
]}

Juang, Yu-Chi ^{[1
]}

O'Donnell, Lara ^{[1
]}

Kumakubo, Ayako ^{[3
]}

Munro, Meagan ^{[1
]}

Sicheri, Frank ^{[1
,4
]}

Gingras, Anne-Claude ^{[1
,4
]}

Natsume, Tohru ^{[5
]}

Suda, Toshio ^{[3
]}

Durocher, Daniel ^{[1
,4
]}

机构：

[1] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[2] Keio Univ, Sch Med, Ctr Integrated Med Res, Shinjuku Ku, Tokyo 1608582, Japan

[3] Keio Univ, Sch Med, Dept Cell Differentiat, Sakaguchi Lab Dev Biol,Shinjuku Ku, Tokyo 1608582, Japan

[4] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[5] Natl Inst Adv Ind Sci & Technol, Biomed Informat Res Ctr, Biol Syst Control Team, Koto Ku, Tokyo 1350064, Japan

来源：

NATURE | 2010年 / 466卷 / 7309期

基金：

加拿大健康研究院;

关键词：

DOUBLE-STRAND BREAKS; STATISTICAL-MODEL; STRUCTURAL BASIS; MAMMALIAN-CELLS; REPAIR PROTEINS; BINDING; COMPLEX; ENZYME; CHAINS; SPECIFICITY;

D O I：

10.1038/nature09297

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

DNA double-strand breaks (DSBs) pose a potent threat to genome integrity. These lesions also contribute to the efficacy of radiotherapy and many cancer chemotherapeutics. DSBs elicit a signalling cascade that modifies the chromatin surrounding the break, first by ATM-dependent phosphorylation and then by RNF8-, RNF168- and BRCA1-dependent regulatory ubiquitination. Here we report that OTUB1, a deubiquitinating enzyme, is an inhibitor of DSB-induced chromatin ubiquitination. Surprisingly, we found that OTUB1 suppresses RNF168-dependent poly-ubiquitination independently of its catalytic activity. OTUB1 does so by binding to and inhibiting UBC13 (also known as UBE2N), the cognate E2 enzyme for RNF168. This unusual mode of regulation is unlikely to be limited to UBC13 because analysis of OTUB1-associated proteins revealed that OTUB1 binds to E2s of the UBE2D and UBE2E subfamilies. Finally, OTUB1 depletion mitigates the DSB repair defect associated with defective ATM signalling, indicating that pharmacological targeting of the OTUB1-UBC13 interaction might enhance the DNA damage response.

引用

页码：941 / U59

页数：8

共 38 条

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