Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
Department of Biochemistry, School of Medicine, Catholic University of Daegu, Daegu, 42472, Republic of Korea.
Cell Death Differ. 2023 Sep;30(9):2151-2166. doi: 10.1038/s41418-023-01208-y. Epub 2023 Aug 18.
The centrosome assembles a bipolar spindle for faithful chromosome segregation during mitosis. To prevent the inheritance of DNA damage, the DNA damage response (DDR) triggers programmed spindle multipolarity and concomitant death in mitosis through a poorly understood mechanism. We identified hornerin, which forms a complex with checkpoint kinase 1 (Chk1) and polo-like kinase 1 (Plk1) to mediate phosphorylation at the polo-box domain (PBD) of Plk1, as the link between the DDR and death in mitosis. We demonstrate that hornerin mediates DDR-induced precocious centriole disengagement through a dichotomous mechanism that includes sequestration of Sgo1 and Plk1 in the cytoplasm through phosphorylation of the PBD in Plk1 by Chk1. Phosphorylation of the PBD in Plk1 abolishes the interaction with Sgo1 and phosphorylation-dependent Sgo1 translocation to the centrosome, leading to precocious centriole disengagement and spindle multipolarity. Mechanistically, hornerin traps phosphorylated Plk1 in the cytoplasm. Furthermore, PBD phosphorylation inactivates Plk1 and disrupts Cep192::Aurora A::Plk1 complex translocation to the centrosome and concurrent centrosome maturation. Remarkably, hornerin depletion leads to chemoresistance against DNA damaging agents by attenuating DDR-induced death in mitosis. These results reveal how the DDR eradicates mitotic cells harboring DNA damage to ensure genome integrity during cell division.
中心体在有丝分裂过程中组装一个两极纺锤体，以确保染色体的正确分离。为了防止 DNA 损伤的遗传，DNA 损伤反应（DDR）通过一种尚未完全了解的机制，触发有丝分裂中纺锤体的多极化和随之而来的程序性细胞死亡。我们鉴定了 hornerin，它与检查点激酶 1（Chk1）和 Polo 样激酶 1（Plk1）形成复合物，介导 Plk1 的 Polo 盒结构域（PBD）的磷酸化，作为 DDR 和有丝分裂中细胞死亡之间的联系。我们证明 hornerin 通过二分机制介导 DDR 诱导的过早中心体脱离，该机制包括通过 Chk1 磷酸化 Plk1 的 PBD 将 Sgo1 和 Plk1 隔离在细胞质中。Plk1 的 PBD 磷酸化会破坏与 Sgo1 的相互作用和磷酸化依赖性 Sgo1 向中心体的易位，导致过早的中心体脱离和纺锤体多极化。从机制上讲，hornerin 将磷酸化的 Plk1 困在细胞质中。此外，PBD 磷酸化使 Plk1 失活，并破坏 Cep192::Aurora A::Plk1 复合物向中心体的易位和中心体的成熟。值得注意的是，hornerin 的耗竭通过减弱 DDR 诱导的有丝分裂细胞死亡，导致对 DNA 损伤剂的化学抗性。这些结果揭示了 DDR 如何消除含有 DNA 损伤的有丝分裂细胞，以确保细胞分裂过程中的基因组完整性。
