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 language | English |
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Journal | Nature Structural and Molecular Biology |
Volume | 19 |
Issue number | 11 |
Pages (from-to) | 1084-92 |
Number of pages | 9 |
ISSN | 1545-9993 |
DOIs | |
Publication status | Published - 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