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

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2012年 / 19卷 / 11期

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

页码：1084 / +

页数：11

共 47 条

[31] The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks [J].