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

• Published in: Nature (London) Vol. 466; no. 7309; pp. 941 - 946
• Main Authors: Nakada, Shinichiro, Durocher, Daniel, Tai, Ikue, Panier, Stephanie, Al-Hakim, Abdallah, Iemura, Shun-ichiro, Juang, Yu-Chi, O'Donnell, Lara, Kumakubo, Ayako, Munro, Meagan, Sicheri, Frank, Gingras, Anne-Claude, Natsume, Tohru, Suda, Toshio
• Format: Journal Article
• Language: English
• Published: LONDON Springer Nature 19.08.2010; Nature Publishing Group
• Subjects: Amino acids; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Cell Line; Cell Line, Tumor; Chemical properties; Chromatin - chemistry; Chromatin - metabolism; Cysteine Endopeptidases - deficiency; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; DNA Breaks, Double-Stranded; DNA damage; DNA repair; DNA Repair - physiology; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Enzymes; Fundamental and applied biological sciences. Psychology; Genetic aspects; Genetics; Humans; Molecular and cellular biology; Molecular genetics; Multidisciplinary Sciences; Mutagenesis. Repair; Mutation; Protein Binding; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Proteins; Science & Technology; Science & Technology - Other Topics; Tumor Suppressor Proteins - antagonists & inhibitors; Tumor Suppressor Proteins - metabolism; Ubiquitin; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin-Conjugating Enzymes - antagonists & inhibitors; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitin-Protein Ligases - antagonists & inhibitors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - physiology; Japan; REPAIR PROTEINS; COMPLEX; ENZYME; SPECIFICITY; STRUCTURAL BASIS; DOUBLE-STRAND BREAKS; CHAINS; MAMMALIAN-CELLS; BINDING; STATISTICAL-MODEL; Double strand break; Chromatin; DNA; Cell component; Inhibition; Lesion; Repair
• DOI: 10.1038/nature09297
• ISSN: 0028-0836

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.