@article{536a7884f8a74522b89032afac77c50c,
title = "Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1",
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.",
author = "Shinichiro Nakada and Ikue Tai and Stephanie Panier and Abdallah Al-Hakim and Iemura, {Shun Ichiro} and Juang, {Yu Chi} and Lara O'Donnell and Ayako Kumakubo and Meagan Munro and Frank Sicheri and Gingras, {Anne Claude} and Tohru Natsume and Toshio Suda and Daniel Durocher",
note = "Funding Information: Acknowledgements We are grateful to T. Ikura, S. Olivarius, R. Sakasai, A. Shibata, T. Oikawa, J. Unno, Y. Katuski, I. Imoto, S. Koyasu, R. Greenberg and the Core Instrumentation Facility, Keio University School of Medicine for technical support and reagents. We also thank R. Szilard and S. Angers for reading the manuscript. Work in the Nakada group in the Suda laboratory is supported by the Promotion of Environmental Improvement for Independence of Young Researchers, {\textquoteleft}Kanrinmaru Project{\textquoteright} from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) Japan, Grant-in-Aid for Young Scientists (Startup 2009, 21870033) from MEXT, Takeda Science Foundation, Mitsubishi Pharma Research Foundation and the Daiwa Anglo-Japanese Foundation. I.T. is supported by MEXT{\textquoteright}s Distinctive University Education Support Program {\textquoteleft}Good Practice{\textquoteright}. Work in the Natsume laboratory is supported by the New Energy and Industrial Technology Development Organization (NEDO). S.P. holds a studentship from the Boehringer Ingelheim Fonds. D.D. is the Thomas Kierans Chair in Mechanisms of Cancer Development and a Canada Research Chair (Tier 2) in Proteomics, Bioinformatics and Functional genomics. Work in the Durocher and Gingras laboratories is supported by grants MOP10703115 (DD) and MOP84314 (ACG) from the Canadian Institutes of Health Research.",
year = "2010",
month = aug,
day = "19",
doi = "10.1038/nature09297",
language = "English",
volume = "466",
pages = "941--946",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7309",
}
