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DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks.
MedLine Citation:
PMID:  23042605     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Ubiquitin-mediated processes orchestrate critical DNA-damage signaling and repair pathways. We identify human DVC1 (C1orf124; Spartan) as a cell cycle-regulated anaphase-promoting complex (APC) substrate that accumulates at stalled replication forks. DVC1 recruitment to sites of replication stress requires its ubiquitin-binding UBZ domain and PCNA-binding PIP box motif but is independent of RAD18-mediated PCNA monoubiquitylation. Via a conserved SHP box, DVC1 recruits the ubiquitin-selective chaperone p97 to blocked replication forks, which may facilitate p97-dependent removal of translesion synthesis (TLS) DNA polymerase η (Pol η) from monoubiquitylated PCNA. DVC1 knockdown enhances UV light-induced mutagenesis, and depletion of human DVC1 or the Caenorhabditis elegans ortholog DVC-1 causes hypersensitivity to replication stress-inducing agents. Our findings establish DVC1 as a DNA damage-targeting p97 adaptor that protects cells from deleterious consequences of replication blocks and suggest an important role of p97 in ubiquitin-dependent regulation of TLS.
Authors:
Anna Mosbech; Ian Gibbs-Seymour; Konstantinos Kagias; Tina Thorslund; Petra Beli; Lou Povlsen; Sofie Vincents Nielsen; Stine Smedegaard; Garry Sedgwick; Claudia Lukas; Rasmus Hartmann-Petersen; Jiri Lukas; Chunaram Choudhary; Roger Pocock; Simon Bekker-Jensen; Niels Mailand
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-07
Journal Detail:
Title:  Nature structural & molecular biology     Volume:  -     ISSN:  1545-9985     ISO Abbreviation:  Nat. Struct. Mol. Biol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101186374     Medline TA:  Nat Struct Mol Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1] Ubiquitin Signaling Group, Department of Disease Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. [2].
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