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USP4 Auto-Deubiquitylation Promotes Homologous Recombination

Repair of DNA double-strand breaks is crucial for maintaining genome integrity and is governed by post-translational modifications such as protein ubiquitylation. Here, we establish that the deubiquitylating enzyme USP4 promotes DNA-end resection and DNA repair by homologous recombination. We also r...

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Autores principales: Wijnhoven, Paul, Konietzny, Rebecca, Blackford, Andrew N., Travers, Jonathan, Kessler, Benedikt M., Nishi, Ryotaro, Jackson, Stephen P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643306/
https://www.ncbi.nlm.nih.gov/pubmed/26455393
http://dx.doi.org/10.1016/j.molcel.2015.09.019
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author Wijnhoven, Paul
Konietzny, Rebecca
Blackford, Andrew N.
Travers, Jonathan
Kessler, Benedikt M.
Nishi, Ryotaro
Jackson, Stephen P.
author_facet Wijnhoven, Paul
Konietzny, Rebecca
Blackford, Andrew N.
Travers, Jonathan
Kessler, Benedikt M.
Nishi, Ryotaro
Jackson, Stephen P.
author_sort Wijnhoven, Paul
collection PubMed
description Repair of DNA double-strand breaks is crucial for maintaining genome integrity and is governed by post-translational modifications such as protein ubiquitylation. Here, we establish that the deubiquitylating enzyme USP4 promotes DNA-end resection and DNA repair by homologous recombination. We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites. Furthermore, we show that USP4 is ubiquitylated on multiple sites including those on cysteine residues and that deubiquitylation of these sites requires USP4 catalytic activity and is required for USP4 to interact with CtIP/MRN and to promote CtIP recruitment and DNA repair. Lastly, we establish that regulation of interactor binding by ubiquitylation occurs more generally among USP-family enzymes. Our findings thus identify USP4 as a novel DNA repair regulator and invoke a model in which ubiquitin adducts regulate USP enzyme interactions and functions.
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spelling pubmed-46433062015-12-08 USP4 Auto-Deubiquitylation Promotes Homologous Recombination Wijnhoven, Paul Konietzny, Rebecca Blackford, Andrew N. Travers, Jonathan Kessler, Benedikt M. Nishi, Ryotaro Jackson, Stephen P. Mol Cell Article Repair of DNA double-strand breaks is crucial for maintaining genome integrity and is governed by post-translational modifications such as protein ubiquitylation. Here, we establish that the deubiquitylating enzyme USP4 promotes DNA-end resection and DNA repair by homologous recombination. We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites. Furthermore, we show that USP4 is ubiquitylated on multiple sites including those on cysteine residues and that deubiquitylation of these sites requires USP4 catalytic activity and is required for USP4 to interact with CtIP/MRN and to promote CtIP recruitment and DNA repair. Lastly, we establish that regulation of interactor binding by ubiquitylation occurs more generally among USP-family enzymes. Our findings thus identify USP4 as a novel DNA repair regulator and invoke a model in which ubiquitin adducts regulate USP enzyme interactions and functions. Cell Press 2015-11-05 /pmc/articles/PMC4643306/ /pubmed/26455393 http://dx.doi.org/10.1016/j.molcel.2015.09.019 Text en © 2015 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wijnhoven, Paul
Konietzny, Rebecca
Blackford, Andrew N.
Travers, Jonathan
Kessler, Benedikt M.
Nishi, Ryotaro
Jackson, Stephen P.
USP4 Auto-Deubiquitylation Promotes Homologous Recombination
title USP4 Auto-Deubiquitylation Promotes Homologous Recombination
title_full USP4 Auto-Deubiquitylation Promotes Homologous Recombination
title_fullStr USP4 Auto-Deubiquitylation Promotes Homologous Recombination
title_full_unstemmed USP4 Auto-Deubiquitylation Promotes Homologous Recombination
title_short USP4 Auto-Deubiquitylation Promotes Homologous Recombination
title_sort usp4 auto-deubiquitylation promotes homologous recombination
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643306/
https://www.ncbi.nlm.nih.gov/pubmed/26455393
http://dx.doi.org/10.1016/j.molcel.2015.09.019
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