The CDC7 kinase is essential for the activation of DNA replication origins and has been implicated in the replication stress response. Using a highly specific chemical inhibitor and a chemical genetic approach, we now show that CDC7 activity is required to coordinate multiple MRE11‐dependent processes occurring at replication forks, independently from its role in origin firing. CDC7 localizes at replication forks and, similarly to MRE11, mediates active slowing of fork progression upon mild topoisomerase inhibition. Both proteins are also retained on stalled forks, where they promote fork processing and restart. Moreover, MRE11 phosphorylation and localization at replication factories are progressively lost upon CDC7 inhibition. Finally, CDC7 activity at reversed forks is required for their pathological MRE11‐dependent degradation in BRCA2‐deficient cells. Thus, upon replication interference CDC7 is a key regulator of fork progression, processing and integrity. These results highlight a dual role for CDC7 in replication, modulating both initiation and elongation steps of DNA synthesis, and identify a key intervention point for anticancer therapies exploiting replication interference.

中文翻译：

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CDC7 激酶促进 MRE11 分叉加工，调节分叉速度和染色体断裂。

CDC7 激酶对于 DNA 复制起点的激活至关重要，并且与复制应激反应有关。使用高度特异性的化学抑制剂和化学遗传方法，我们现在表明 CDC7 活性是协调在复制叉上发生的多个 MRE11 依赖性过程所必需的，与其在起源激发中的作用无关。CDC7 定位于复制叉，并且与 MRE11 类似，介导在轻度拓扑异构酶抑制后主动减缓叉进展。这两种蛋白质也保留在停滞的叉子上，在那里它们促进叉子的加工和重新启动。此外，复制工厂的 MRE11 磷酸化和定位在 CDC7 抑制后逐渐丧失。最后，CDC7 在 BRCA2 缺陷细胞中的病理性 MRE11 依赖性降解是必需的。因此，在复制干扰时，CDC7 是分叉进程、处理和完整性的关键调节器。这些结果突出了 CDC7 在复制中的双重作用，调节 DNA 合成的起始和延伸步骤，并确定了利用复制干扰的抗癌疗法的关键干预点。