DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks

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

doi:10.1038/nsmb.2395

DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks

Nat Struct Mol Biol. 2012 Nov;19(11):1084-92. doi: 10.1038/nsmb.2395. Epub 2012 Oct 7.

Authors

Anna Mosbech¹, 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

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.

PMID: 23042605
DOI: 10.1038/nsmb.2395

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / metabolism*
Anaphase-Promoting Complex-Cyclosome
Animals
Caenorhabditis elegans
Cell Cycle Proteins / metabolism*
DNA Damage / genetics*
DNA Replication / genetics
DNA Replication / physiology*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
DNA-Directed DNA Polymerase / metabolism
Flow Cytometry
Gene Knockdown Techniques
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Humans
Immunoblotting
Immunoprecipitation
Mass Spectrometry
Mutagenesis
Plasmids / genetics
Plasmids / metabolism
Proliferating Cell Nuclear Antigen / metabolism
RNA Interference
RNA, Small Interfering / genetics
Signal Transduction / genetics
Signal Transduction / physiology*
Ubiquitin / metabolism*
Ubiquitin-Protein Ligase Complexes / metabolism*
Valosin Containing Protein

Substances

Cell Cycle Proteins
DNA-Binding Proteins
Proliferating Cell Nuclear Antigen
RNA, Small Interfering
SPRTN protein, human
Ubiquitin
enhanced green fluorescent protein
Green Fluorescent Proteins
Ubiquitin-Protein Ligase Complexes
Anaphase-Promoting Complex-Cyclosome
DNA-Directed DNA Polymerase
Rad30 protein
Adenosine Triphosphatases
Valosin Containing Protein