FBH1 Catalyzes Regression of Stalled Replication Forks

被引:71
|
作者
Fugger, Kasper [1 ]
Mistrik, Martin [2 ]
Neelsen, Kai J. [3 ]
Yao, Qi [4 ]
Zellweger, Ralph [3 ]
Kousholt, Arne Nedergaard [1 ]
Haahr, Peter [1 ]
Chu, Wai Kit [4 ]
Bartek, Jiri [2 ,5 ]
Lopes, Massimo [3 ]
Hickson, Ian D. [4 ]
Sorensen, Claus Storgaard [1 ]
机构
[1] Univ Copenhagen, Biotech Res & Innovat Ctr, DK-2200 Copenhagen N, Denmark
[2] Palacky Univ, Fac Med & Dent, Inst Mol & Translat Med, Olomouc 77900, Czech Republic
[3] Univ Zurich, Inst Mol Canc Res, CH-8057 Zurich, Switzerland
[4] Univ Copenhagen, Panum Inst, Dept Cellular & Mol Med, Ctr Hlth Aging, DK-2200 Copenhagen N, Denmark
[5] Danish Canc Soc Res Ctr, DK-2100 Copenhagen O, Denmark
来源
CELL REPORTS | 2015年 / 10卷 / 10期
基金
新加坡国家研究基金会; 欧洲研究理事会; 瑞士国家科学基金会; 英国医学研究理事会;
关键词
DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; HOMOLOGOUS RECOMBINATION; MAMMALIAN-CELLS; HELICASE; RESTART; RECOGNITION; CONTRIBUTES; MAINTENANCE; STRESS;
D O I
10.1016/j.celrep.2015.02.028
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
DNA replication fork perturbation is a major challenge to the maintenance of genome integrity. It has been suggested that processing of stalled forks might involve fork regression, in which the fork reverses and the two nascent DNA strands anneal. Here, we show that FBH1 catalyzes regression of a model replication fork in vitro and promotes fork regression in vivo in response to replication perturbation. Cells respond to fork stalling by activating checkpoint responses requiring signaling through stress-activated protein kinases. Importantly, we show that FBH1, through its helicase activity, is required for early phosphorylation of ATM substrates such as CHK2 and CtIP as well as hyperphosphorylation of RPA. These phosphorylations occur prior to apparent DNA double-strand break formation. Furthermore, FBH1-dependent signaling promotes checkpoint control and preserves genome integrity. We propose a model whereby FBH1 promotes early checkpoint signaling by remodeling of stalled DNA replication forks.
引用
收藏
页码:1749 / 1757
页数:9
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