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.

The E3 ubiquitin ligase TRAIP associates with replication forks through direct interaction with PCNA, promoting checkpoint signaling and genome stability after replication stress.

Background:The biological function of the ASB family of ubiquitin ligases is poorly characterized. Results: A family-wide analysis of ASB-associated proteins by mass spectrometry identified novel interactors. Conclusion: ASB proteins can associate in multimeric complexes. Asb11 ubiquitinates Ribophorin 1 and regulates its turnover. Significance: This data resource will facilitate the characterization of the biological function of ASB proteins.