title: DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks.
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.
authors.affiliation: Ubiquitin Signaling Group, Department of Disease Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anna
authors.initials: A
authors.lastname: Mosbech
authors.forename: Ian
authors.initials: I
authors.lastname: Gibbs-Seymour
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kagias
authors.forename: Tina
authors.initials: T
authors.lastname: Thorslund
authors.forename: Petra
authors.initials: P
authors.lastname: Beli
authors.forename: Lou
authors.initials: L
authors.lastname: Povlsen
authors.forename: Sofie Vincents
authors.initials: SV
authors.lastname: Nielsen
authors.forename: Stine
authors.initials: S
authors.lastname: Smedegaard
authors.forename: Garry
authors.initials: G
authors.lastname: Sedgwick
authors.forename: Claudia
authors.initials: C
authors.lastname: Lukas
authors.forename: Rasmus
authors.initials: R
authors.lastname: Hartmann-Petersen
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Chunaram
authors.initials: C
authors.lastname: Choudhary
authors.forename: Roger
authors.initials: R
authors.lastname: Pocock
authors.forename: Simon
authors.initials: S
authors.lastname: Bekker-Jensen
authors.forename: Niels
authors.initials: N
authors.lastname: Mailand
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D017173:Caenorhabditis elegans; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D016296:Mutagenesis; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D000074405:Valosin Containing Protein; D000099270:Y-Family DNA Polymerases
chemical_list: D000251:Adenosine Triphosphatases; D064173:Anaphase-Promoting Complex-Cyclosome; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D049452:Green Fluorescent Proteins; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D025801:Ubiquitin; D043743:Ubiquitin-Protein Ligase Complexes; D000074405:Valosin Containing Protein; C574636:SPRTN protein, human; C485184:enhanced green fluorescent protein; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases