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

Anna Mosbech, Ian Gibbs-Seymour, Konstantinos Kagias, Tina Thorslund, Petra Beli, Lou Klitgaard Povlsen, Sofie V Nielsen, Stine K Smedegaard, Garry G Sedgwick, Claudia Lukas, Rasmus Hartmann-Petersen, Jiri Lukas, Chuna R Choudhary, Roger D J Pocock, Simon Bekker-Jensen, Niels Mailand

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119 Citations (Scopus)

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 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.
Original languageEnglish
Pages (from-to)1084 - 1092
Number of pages9
JournalNature Structural & Molecular Biology
Volume19
Issue number11
DOIs
Publication statusPublished - 2012
Externally publishedYes

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