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 and Daniel Durocher ()
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Shinichiro Nakada: Center of Integrated Medical Research, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
Ikue Tai: Center of Integrated Medical Research, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
Stephanie Panier: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Abdallah Al-Hakim: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Shun-ichiro Iemura: Biological Systems Control Team, Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan
Yu-Chi Juang: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Lara O’Donnell: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Ayako Kumakubo: The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
Meagan Munro: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Frank Sicheri: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Anne-Claude Gingras: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Tohru Natsume: Biological Systems Control Team, Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan
Toshio Suda: The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan
Daniel Durocher: Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Nature, 2010, vol. 466, issue 7309, 941-946

Abstract: 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.

Date: 2010
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DOI: 10.1038/nature09297

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