DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks
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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.
|Journal||Nature Structural and Molecular Biology|
|Number of pages||9|
|Publication status||Published - 2012|
- 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