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, Chuna Ram Choudhary, Roger David John Pocock, Simon Bekker-Jensen, Niels Mailand

Research output: Contribution to journalJournal articleResearchpeer-review

148 Citations (Scopus)

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.
Original languageEnglish
JournalNature Structural and Molecular Biology
Volume19
Issue number11
Pages (from-to)1084-92
Number of pages9
ISSN1545-9993
DOIs
Publication statusPublished - 2012

Keywords

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

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