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.
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A mutant ubiquitin K63R completely abolishes UBC13/UEV1a-mediated ubiquitin chain formation independently of the RING domain.
“a mutant ubiquitin in which lysine 63 is replaced by an arginine (K63R) completely abolished UBC13/ UEV1a-mediated ubiquitin chain formation independently of the RING domain (19,20) (Fig. 4A).”
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- Authors
- Nakada, S., Tai, I., Panier, S., Al-Hakim, A., Iemura, S.-I., Juang, Y.-C., O’Donnell, L., Kumakubo, A., Munro, M., Sicheri, F., Gingras, A.-C., Natsume, T., Suda, T., & Durocher, D.
- Affiliations
- Keio University (JP)
- Mount Sinai Hospital (CA)
- National Institute of Advanced Industrial Science and Technology (JP)
- Corresponding author
- Nakada, Shinichiro
- Durocher, Daniel
- Venue
- Nature
- Published
- 2010-08
- Volume
- 466
- Issue
- 7309
- Pages
- 941-946
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2021565943
- Cited by
- 357
- References
- 1
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 23 · 2023: 15 · 2022: 17 · 2021: 19 · 2020: 26 · 2019: 20 · 2018: 14 · 2017: 21 · 2016: 24 · 2015: 26 · 2014: 22 · 2013: 33 · 2012: 36
- FWCI
- 12.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Canadian Institutes of Health Research (MOP10703115, MOP 84314)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- OTUB1, deubiquitinase, DNA double-strand breaks, DNA damage response, RNF168, Ubc13, E2 ubiquitin-conjugating enzyme, ATM signalling, histone ubiquitination, DNA repair, BRCA1, RNF8
- MeSH terms
- Deubiquitinating Enzymes, Cell Line, Chromatin, Cysteine Endopeptidases, DNA Repair, DNA-Binding Proteins, Humans, Protein Binding, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Cell Line, Tumor, DNA Breaks, Double-Stranded, Ubiquitination, Ataxia Telangiectasia Mutated Proteins
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