RIF1 controls replication initiation and homologous recombination repair in a radiation dose-dependent manner
RIF1 controls replication initiation and homologous recombination repair in a radiation dose-dependent manner
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RIF1以辐射剂量依赖性方式控制复制起始和同源重组修复
DOI：
10.1242/jcs.240036
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发表时间：
2020-05
影响因子：
4
通讯作者：
Yuichiro Saito;J. Kobayashi;Masato T. Kanemaki;K. Komatsu
中科院分区：
文献类型：
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作者：
Yuichiro Saito;J. Kobayashi;Masato T. Kanemaki;K. Komatsu
RIF1控制DNA复制时间和DNA双链断裂（DSB）修复途径，以维持基因组完整性。然而，在暴露于电离辐射（IR）后，RIF1如何将这两个过程联系起来尚不清楚。在这里，我们发现RIF1对同源重组修复（HRR）的抑制以剂量依赖的方式发生，并通过DNA复制控制。暴露于高剂量IR后，RIF1抑制DNA末端切除和RAD51积累。相反，低剂量IR暴露后，RIF1对HRR的抑制作用被BRCA1拮抗。在高IR剂量下，RIF1通过去磷酸化MCM解旋酶抑制复制起始。值得注意的是，即使没有RIF1， MCM解旋酶的去磷酸化也会抑制DNA末端切除和HRR。因此，我们的数据显示了活跃的DNA复制对HRR的重要性，并提出了高IR剂量下DNA复制和HRR的共同抑制机制，这两者都由RIF1控制。本文以第一人称采访了该论文的第一作者。摘要：辐照对同源重组修复（HRR）的抑制呈剂量依赖性。RIF1通过控制复制起始在这种剂量依赖性的HRR抑制中发挥作用。
ABSTRACT RIF1 controls both DNA replication timing and the DNA double-strand break (DSB) repair pathway to maintain genome integrity. However, it remains unclear how RIF1 links these two processes following exposure to ionizing radiation (IR). Here, we show that inhibition of homologous recombination repair (HRR) by RIF1 occurs in a dose-dependent manner and is controlled via DNA replication. RIF1 inhibits both DNA end resection and RAD51 accumulation after exposure to high doses of IR. Contrastingly, HRR inhibition by RIF1 is antagonized by BRCA1 after a low-dose IR exposure. At high IR doses, RIF1 suppresses replication initiation by dephosphorylating MCM helicase. Notably, the dephosphorylation of MCM helicase inhibits both DNA end resection and HRR, even without RIF1. Thus, our data show the importance of active DNA replication for HRR and suggest a common suppression mechanism for DNA replication and HRR at high IR doses, both of which are controlled by RIF1. This article has an associated First Person interview with the first author of the paper. Summary: Homologous recombination repair (HRR) is suppressed by radiation exposure in a dose-dependent manner. RIF1 has a role in this dose-dependent suppression of HRR by controlling replication initiation.