Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 19, Issue 11, Pages 1084-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2395
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Funding
- Novo Nordisk Foundation
- Danish Medical Research Council
- Danish Cancer Society
- Lundbeck Foundation
- Danish National Research Foundation
- European Research Council
- Lundbeck Foundation [R34-2009-3790] Funding Source: researchfish
- Novo Nordisk Foundation Center for Protein Research [PI Chunaram Choudhary, PI Niels Mailand] Funding Source: researchfish
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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 eta (Pol eta) 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.
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