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

Shinichiro Nakada, Ikue Tai, Stephanie Panier, Abdallah Al-Hakim, Shun Ichiro Iemura, Yu Chi Juang, Lara O'Donnell, Ayako Kumakubo, Meagan Munro, Frank Sicheri, Anne Claude Gingras, Tohru Natsume, Toshio Suda, Daniel Durocher

Research output: Contribution to journalArticlepeer-review

228 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)941-946
Number of pages6
JournalNature
Volume466
Issue number7309
DOIs
Publication statusPublished - 2010 Aug 19

ASJC Scopus subject areas

  • General

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