Upon replication fork arrest, the replication checkpoint kinase Cds1 is stimulated to preserve genome integrity. Robust activation of Cds1 in response to hydroxyurea prevents the endonuclease Mus81 from cleaving the stalled replication fork inappropriately. However, we find that the response is different in temperature-sensitive mcm4 mutants, affecting a subunit of the MCM replicative helicase. We show that Cds1 inhibition of Mus81 promotes genomic instability and allows mcm4-dg cells to evade cell cycle arrest. Cds1 regulation of Mus81 activity also contributes to the formation of the replication stress-induced DNA damage markers replication protein A (RPA) and Ku. These results identify a surprising role for Cds1 in driving DNA damage and disrupted chromosomal segregation under certain conditions of replication stress.

中文翻译：

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主动复制检查点可驱动裂变酵母mcm4突变体中的基因组不稳定。

复制叉停滞后，复制检查点激酶Cds1受到刺激以保持基因组完整性。Cds1对羟基脲的强烈激活可防止核酸内切酶Mus81不适当地切割停滞的复制叉。但是，我们发现该响应在温度敏感的mcm4突变体中有所不同，从而影响MCM复制解旋酶的一个亚基。我们显示，Cds1对Mus81的抑制作用会促进基因组不稳定性，并使mcm4-dg细胞逃避细胞周期停滞。Cds1对Mus81活性的调节也有助于复制应激诱导的DNA损伤标志物复制蛋白A（RPA）和Ku的形成。这些结果表明在某些复制压力条件下，Cds1在驱动DNA损伤和破坏染色体分离方面具有令人惊讶的作用。