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PMID: 20725033 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature ·Vol. 466 ·No. 7309 ·2010-08-19 ·Pages 941-6

Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang YC, O'Donnell L, Kumakubo A, Munro M, Sicheri F, Gingras AC, Natsume T, Suda T, Durocher D

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.

MeSH Terms
Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/antagonists & inhibitors,metabolism Cell Line Cell Line, Tumor Chromatin/chemistry,metabolism Cysteine Endopeptidases/deficiency,genetics,metabolism DNA Breaks, Double-Stranded DNA Repair/physiology DNA-Binding Proteins/antagonists & inhibitors,metabolism Deubiquitinating Enzymes Humans Protein Binding Protein Serine-Threonine Kinases/antagonists & inhibitors,metabolism Tumor Suppressor Proteins/antagonists & inhibitors,metabolism Ubiquitin/genetics,metabolism Ubiquitin-Conjugating Enzymes/antagonists & inhibitors,metabolism Ubiquitin-Protein Ligases/antagonists & inhibitors,genetics,metabolism Ubiquitination/physiology
Chemicals
Cell Cycle Proteins Chromatin DNA-Binding Proteins Tumor Suppressor Proteins Ubiquitin UBE2N protein, human Ubiquitin-Conjugating Enzymes RNF168 protein, human Ubiquitin-Protein Ligases ATM protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Deubiquitinating Enzymes OTUB1 protein, human Cysteine Endopeptidases
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Nakada Shinichiro
Center of Integrated Medical Research, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan. [email protected]
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
Durocher Daniel
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature09297
Email
[email protected]
Published
2010-08-19
Pages
941-6
Language
English
Region
England
NLM ID
0410462
Subset
IM
Grants
Canadian Institutes of Health Research · MOP10703115 · Canada
Canadian Institutes of Health Research · MOP84314 · Canada
Corrections
CommentIn
PMID: 20725029
External Links
PubMed source DOI: 10.1038/nature09297 View journal details
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