DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks

作者：Mo**ech Anna; Gibbs Seymour Ian; Kagias Konstantinos; Thorslund Tina; Beli Petra; Povlsen Lou; Nielsen Sofie Vincents; Smedegaard Stine; Sedgwick Garry; Lukas Claudia; Hartmann Petersen Rasmus; Lukas Jiri; Choudhary Chunaram; Pocock Roger; Bekker Jensen Simon; Mailand Niels^*

来源：Nature Structural & Molecular Biology, 2012, 19(11): 1084-+.

DOI：10.1038/nsmb.2395

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.

• 出版日期2012-11