法国居里研究所Raphael Ceccaldi小组发现，Polθ被PLK1磷酸化来修复有丝分裂中的双链断裂。相关论文于2023年9月6日在线发表在《自然》杂志上。

研究人员发现DNA聚合酶θ（Polθ）能修复有丝分裂的DNA双链断裂（DSB），从而维持基因组的完整性。与其他DSB修复因子不同，Polθ的功能在有丝分裂过程中被类Polo激酶1（PLK1）磷酸化后激活。磷酸化的Polθ通过与TOPBP1的BRCA1 C端结构域直接相互作用被招募到有丝分裂的DSB处，并在那里介导断裂DNA末端的连接。Polθ缺失会导致有丝分裂DSB修复缺陷，从而导致基因组完整性丧失。在缺乏同源重组的细胞中，这种情况会进一步恶化，Polθ对有丝分裂DSB修复的缺失会导致细胞死亡。

这些研究结果表明，有丝分裂DSB修复是Polθ与同源重组之间合成致死的根本原因。这些发现共同揭示了有丝分裂DSB修复在维持基因组完整性中的关键重要性。

据介绍，DSB是对基因组完整性构成挑战的有害损伤。为了减轻这种威胁，人类细胞依赖于多种DNA修复机制的活动，这些机制在整个细胞周期中都受到严格调控。在间期，DSB主要通过非同源末端连接和同源重组进行修复。然而，这些途径在有丝分裂过程中被完全抑制，导致有丝分裂DSB的命运不明。

附：英文原文

Title: Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis

Author: Gelot, Camille, Kovacs, Marton Tibor, Miron, Simona, Mylne, Emilie, Haan, Alexis, Boeffard-Dosierre, Liza, Ghouil, Rania, Popova, Tatiana, Dingli, Florent, Loew, Damarys, Guirouilh-Barbat, Jose, Del Nery, Elaine, Zinn-Justin, Sophie, Ceccaldi, Raphael

Issue&Volume: 2023-09-06

Abstract: DNA double-strand breaks (DSBs) are deleterious lesions that challenge genome integrity. To mitigate this threat, human cells rely on the activity of multiple DNA repair machineries that are tightly regulated throughout the cell cycle1. In interphase, DSBs are mainly repaired by non-homologous end joining and homologous recombination2. However, these pathways are completely inhibited in mitosis3–5, leaving the fate of mitotic DSBs unknown. Here we show that DNA polymerase theta6 (Polθ) repairs mitotic DSBs and thereby maintains genome integrity. In contrast to other DSB repair factors, Polθ function is activated in mitosis upon phosphorylation by Polo-like kinase 1 (PLK1). Phosphorylated Polθ is recruited by a direct interaction with the BRCA1 C-terminal domains of TOPBP1 to mitotic DSBs, where it mediates joining of broken DNA ends. Loss of Polθ leads to defective repair of mitotic DSBs, resulting in a loss of genome integrity. This is further exacerbated in cells that are deficient in homologous recombination, where loss of mitotic DSB repair by Polθ results in cell death. Our results identify mitotic DSB repair as the underlying cause of synthetic lethality between Polθ and homologous recombination. Together, our findings reveal the critical importance of mitotic DSB repair in the maintenance of genome integrity. In mitosis, genome integrity is maintained by DNA polymerase theta-dependent repair of DNA double-strand breaks, which is regulated by Polo-like kinase 1 activity.

DOI: 10.1038/s41586-023-06506-6

Source: https://www.nature.com/articles/s41586-023-06506-6