Document Detail


The deubiquitylating enzyme USP44 counteracts the DNA double-strand break response mediated by the RNF8 and RNF168 ubiquitin ligases.
MedLine Citation:
PMID:  23615962     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Protein recruitment to DNA double-strand breaks (DSBs) relies on ubiquitylation of the surrounding chromatin by the RING finger ubiquitin ligases RNF8 and RNF168. Flux through this pathway is opposed by several deubiquitylating enzymes (DUBs), including OTUB1 and USP3. By analyzing the effect of individually overexpressing the majority of human DUBs on RNF8/RNF168-mediated 53BP1 retention at DSB sites, we found that USP44 and USP29 powerfully inhibited this response at the level of RNF168 accrual. Both USP44 and USP29 promoted efficient deubiquitylation of histone H2A, but unlike USP44, USP29 displayed nonspecific reactivity toward ubiquitylated substrates. Moreover, USP44 but not other H2A DUBs was recruited to RNF168-generated ubiquitylation products at DSB sites. Individual depletion of these DUBs only mildly enhanced accumulation of ubiquitin conjugates and 53BP1 at DSBs, suggesting considerable functional redundancy among cellular DUBs that restrict ubiquitin-dependent protein assembly at DSBs. Our findings implicate USP44 in negative regulation of the RNF8/RNF168 pathway and illustrate the usefulness of DUB overexpression screens for identification of antagonizers of ubiquitin-dependent cellular responses.
Authors:
Anna Mosbech; Claudia Lukas; Simon Bekker-Jensen; Niels Mailand
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-04-24
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-10     Completed Date:  2013-08-12     Revised Date:  2014-06-10    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16579-87     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Cell Line
Cysteine Endopeptidases / genetics,  metabolism
DNA Breaks, Double-Stranded*
DNA-Binding Proteins / genetics,  metabolism*
Endopeptidases / genetics,  metabolism*
Humans
Intracellular Signaling Peptides and Proteins / genetics,  metabolism
Ubiquitin / genetics,  metabolism*
Ubiquitin-Protein Ligases / genetics,  metabolism*
Ubiquitin-Specific Proteases
Ubiquitination / physiology*
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/RNF8 protein, human; 0/TP53BP1 protein, human; 0/USP29 protein, human; 0/USP3 protein, human; 0/Ubiquitin; EC 3.4.-/Endopeptidases; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.22.-/otubain 1 protein, human; EC 3.4.99-/Ubiquitin-Specific Proteases; EC 6.3.2.19/RNF168 protein, human; EC 6.3.2.19/Ubiquitin-Protein Ligases
Comments/Corrections

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