共 47 条
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
相关论文