Replication fork progression is being continuously hampered by exogenously introduced and naturally occurring DNA lesions and other physical obstacles. Checkpoint kinase 1 (Chk1) is activated at replication forks that encounter damaged DNA. Subsequently, 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. Indeed, such findings have unveiled a puzzling connection between Chk1 and DNA lesion bypass, which might be central to promoting fork elongation and checkpoint attenuation. In summary, Chk1 is a multifaceted and versatile signaling factor that acts at ongoing forks and replication origins to determine the extent and quality of the cellular response to replication stress.

中文翻译：

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叉子和激酶：从CHK1角度看DNA复制的故事。

复制叉的前进不断受到外源性引入和自然发生的DNA损伤以及其他物理障碍的阻碍。Checkpoint激酶1（Chk1）在遇到受损DNA的复制叉处被激活。随后，Chk1抑制了新复制工厂的启动，并激发了休眠来源（停滞货叉附近的来源）的发射。Chk1还避免了前叉塌陷成DSB（双链断裂）并促进了前叉的伸长。在分子水平上，当前模型将停滞的叉子视为Chk1活化的位点，将核质视为Chk1磷酸化靶蛋白的位置。该模型无疑可以解释Chk1如何调节原点射击，但还不清楚Chk1如何控制停滞叉的命运。有趣的是，最近的报道表明，Chk1使染色质结合蛋白磷酸化，甚至具有不依赖激酶的功能，这可能揭示了Chk1如何促进受损DNA的延伸。确实，这些发现揭露了Chk1与DNA损伤旁路之间令人费解的联系，这可能对促进叉子延长和检查点衰减至关重要。总之，Chk1是一个多方面的通用信号转导因子，可作用于正在进行的分叉和复制起点，以确定细胞对复制应激的反应的程度和质量。这可能对提升货叉伸长和检查点衰减至关重要。总之，Chk1是一个多方面的通用信号转导因子，可作用于正在进行的分叉和复制起点，以确定细胞对复制应激的反应的程度和质量。这可能对提升货叉伸长和检查点衰减至关重要。总之，Chk1是一个多方面的通用信号转导因子，可作用于正在进行的分叉和复制起点，以确定细胞对复制应激的反应的程度和质量。