Proper chromosome segregation is crucial for preserving genomic integrity, and errors in this process cause chromosome mis-segregation, which may contribute to cancer development. Sister chromatid separation is triggered by Separase, an evolutionary conserved protease that cleaves the cohesin complex, allowing the dissolution of sister chromatid cohesion. Here we provide evidence that Separase participates in genomic stability maintenance by controlling replication fork speed. We found that Separase interacted with the replication licensing factors MCM2–7, and genome-wide data showed that Separase co-localized with MCM complex and cohesin. Unexpectedly, the depletion of Separase increased the fork velocity about 1.5-fold and caused a strong acetylation of cohesin's SMC3 subunit and altered checkpoint response. Notably, Separase silencing triggered genomic instability in both HeLa and human primary fibroblast cells. Our results show a novel mechanism for fork progression mediated by Separase and thus the basis for genomic instability associated with tumorigenesis.

中文翻译：

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Separase通过控制复制叉的速度来防止基因组不稳定

正确的染色体分离对于保持基因组完整性至关重要，并且此过程中的错误会导致染色体错误分离，这可能有助于癌症的发展。姊妹染色单体的分离是由Separase触发的，Separase是一种进化保守的蛋白酶，可裂解黏附素复合物，从而使姊妹染色单体的凝聚力得以溶解。在这里，我们提供了证明Separase通过控制复制叉速度来参与基因组稳定性维护的证据。我们发现Separase与复制许可因子MCM2-7相互作用，并且全基因组数据显示Separase与MCM复合物和黏附素共定位。出乎意料的是，分离酶的耗竭叉速增加了约1.5倍，并导致粘着蛋白的SMC3亚基强烈乙酰化，并改变了检查点反应。值得注意的是，Separase沉默会在HeLa和人类原代成纤维细胞中引发基因组不稳定。我们的研究结果显示了由Separase介导的叉子进展的新机制，因此是与肿瘤发生相关的基因组不稳定性的基础。