FBH1 Catalyzes Regression of Stalled Replication Forks
FBH1 Catalyzes Regression of Stalled Replication Forks
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DOI：
10.1016/j.celrep.2015.02.028
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发表时间：
2015-03-17
期刊：
影响因子：
8.8
通讯作者：
Sorensen, Claus Storgaard
中科院分区：
文献类型：
--
作者：
Fugger, Kasper;Mistrik, Martin;Sorensen, Claus Storgaard
DNA复制叉扰动是维持基因组完整性的主要挑战。有人认为，停滞的分叉的处理可能涉及分叉回归，其中分叉逆转，两条新生DNA链退火。在这里，我们表明，FBH1催化模型复制叉在体外回归，并促进叉在体内回归复制扰动。细胞通过激活检查点反应来响应叉停滞，所述检查点反应需要通过应激激活蛋白激酶进行信号传导。重要的是，我们发现FBH1通过其解旋酶活性，是ATM底物如CHK2和CtIP的早期磷酸化以及RPA的过度磷酸化所必需的。这些磷酸化发生在明显的DNA双链断裂形成之前。此外，FBH1依赖性信号促进检查点控制并保持基因组完整性。我们提出了一个模型，FBH1通过重塑停滞的DNA复制叉来促进早期检查点信号传导。
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.