The fork and the kinase: a DNA replication tale from a CHK1 perspective.
The fork and the kinase: a DNA replication tale from a CHK1 perspective.
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DOI：
10.1016/j.mrrev.2014.10.003
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发表时间：
2015-01
期刊：
影响因子：
--
通讯作者：
Gottifredi V
中科院分区：
文献类型：
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作者：
González Besteiro MA;Gottifredi V
复制叉进展不断受到外源引入和自然发生的DNA损伤和其他物理障碍的阻碍。检查点激酶1（Chk1）在遇到受损DNA的复制叉处被激活。Chk1抑制新复制工厂的启动，并刺激休眠起点（停滞分叉附近的起点）的启动。Chk1还避免了叉折叠成DSB（双链断裂）并促进叉伸长。在分子水平上，目前的模型认为停滞叉作为Chk1激活的位点，核质作为Chk1磷酸化靶蛋白的位置。这个模型当然可以解释Chk1如何调节起源放电，但Chk1如何控制停滞分叉的命运还不太清楚。有趣的是，最近的报告表明，Chk1磷酸化染色质结合蛋白，甚至拥有激酶独立的功能可能揭示了Chk1如何有助于受损DNA的延伸。这些发现揭示了Chk1和DNA损伤旁路之间令人困惑的联系，这可能是促进分叉延长和检查点衰减的核心。总之，Chk 1在进行中的分叉和复制起点的多方面和多功能决定了细胞对复制应激反应的程度和质量。
Replication fork progression is being continuously hampered by exogenously introduced and naturally occurring DNA lesions and other physical obstacles. The checkpoint kinase 1 (Chk1) is activated at replication forks that encounter damaged-DNA. Chk1 inhibits the initiation of new replication factories and stimulates the firing of dormant origins (those in the vicinity of stalled forks). Chk1 also avoids fork collapse into DSBs (double strand breaks) and promotes fork elongation. At the molecular level, the current model considers stalled forks as the site of Chk1 activation and the nucleoplasm as the location where Chk1 phosphorylates target proteins. This model certainly serves to explain how Chk1 modulates origin firing, but how Chk1 controls the fate of stalled forks is less clear. Interestingly, recent reports demonstrating that Chk1 phosphorylates chromatin-bound proteins and even holds kinase-independent functions might shed light on how Chk1 contributes to the elongation of damaged DNA. Such findings unveil a puzzling connection between Chk1 and DNA-lesion bypass, which might be central to promoting fork elongation and checkpoint attenuation. In summary, the multifaceted and versatile functions of Chk1 at ongoing forks and replication origins determine the extent and quality of the cellular response to replication stress.