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

被引:144
作者
Mosbech, Anna [1 ]
Gibbs-Seymour, Ian [1 ]
Kagias, Konstantinos [2 ]
Thorslund, Tina [1 ]
Beli, Petra [3 ]
Povlsen, Lou [1 ]
Nielsen, Sofie Vincents [4 ]
Smedegaard, Stine [1 ]
Sedgwick, Garry
Lukas, Claudia [5 ,6 ]
Hartmann-Petersen, Rasmus [4 ]
Lukas, Jiri [5 ,6 ]
Choudhary, Chunaram [3 ]
Pocock, Roger [2 ]
Bekker-Jensen, Simon [1 ]
Mailand, Niels [1 ]
机构
[1] Univ Copenhagen, Fac Hlth Sci, Novo Nordisk Fdn Ctr Prot Res, Ubiquitin Signaling Grp,Dept Dis Biol, Copenhagen, Denmark
[2] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark
[3] Univ Copenhagen, Fac Hlth Sci, Novo Nordisk Fdn Ctr Prot Res, Dept Prote, Copenhagen, Denmark
[4] Univ Copenhagen, Dept Biol, Copenhagen, Denmark
[5] Danish Canc Soc Res Ctr, Ctr Genotox Stress Res, Copenhagen, Denmark
[6] Danish Canc Soc Res Ctr, Chromosome Biol Unit, Copenhagen, Denmark
基金
欧洲研究理事会; 英国医学研究理事会; 新加坡国家研究基金会;
关键词
TRANSLESION SYNTHESIS; POLYMERASE-ETA; AAA-ATPASE; PCNA; REGULATOR; BINDING; TOLERANCE; DOMAIN; 53BP1;
D O I
10.1038/nsmb.2395
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1084 / +
页数:11
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