Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan
Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan.
J Cell Sci. 2020 Jun 22;133(12):jcs240036. doi: 10.1242/jcs.240036.
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.
RIF1 控制着 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，RIF1 在暴露于电离辐射（IR）后如何将这两个过程联系起来仍不清楚。在这里，我们表明 RIF1 通过 DNA 复制以剂量依赖的方式抑制同源重组修复（HRR）。RIF1 在暴露于高剂量 IR 后抑制 DNA 末端切除和 RAD51 积累。相比之下，BRCA1 拮抗 RIF1 在低剂量 IR 暴露后的 HRR 抑制。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，MCM 解旋酶的去磷酸化抑制 DNA 末端切除和 HRR，即使没有 RIF1 也是如此。因此，我们的数据表明活跃的 DNA 复制对 HRR 的重要性，并表明在高 IR 剂量下 DNA 复制和 HRR 的共同抑制机制，这两者均受 RIF1 控制。本文有与论文第一作者的相关第一人称采访。
