Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
Sci Adv. 2019 Mar 6;5(3):eaau7566. doi: 10.1126/sciadv.aau7566. eCollection 2019 Mar.
Polo-like kinase 1 (Plk1) is a crucial regulator of cell cycle progression; but the mechanism of regulation of Plk1 activity is not well understood. We present evidence that Plk1 activity is controlled by a balanced methylation and phosphorylation switch. The methyltransferase G9a monomethylates Plk1 at Lys209, which antagonizes phosphorylation of T210 to inhibit Plk1 activity. We found that the methyl-deficient Plk1 mutant K209A affects DNA replication, whereas the methyl-mimetic Plk1 mutant K209M prolongs metaphase-to-anaphase duration through the inability of sister chromatids separation. We detected accumulation of Plk1 K209me1 when cells were challenged with DNA damage stresses. Ablation of K209me1 delays the timely removal of RPA2 and RAD51 from DNA damage sites, indicating the critical role of K209me1 in guiding the machinery of DNA damage repair. Thus, our study highlights the importance of a methylation-phosphorylation switch of Plk1 in determining its kinase activity and functioning in DNA damage repair.
丝氨酸/苏氨酸激酶 Polo-like 激酶 1（Plk1）是细胞周期进程的关键调节因子；但 Plk1 活性的调节机制尚不清楚。我们提出证据表明，Plk1 活性受甲基化和磷酸化平衡开关控制。甲基转移酶 G9a 将 Plk1 赖氨酸 209 单甲基化，拮抗 T210 的磷酸化，从而抑制 Plk1 活性。我们发现，缺乏甲基的 Plk1 突变体 K209A 会影响 DNA 复制，而甲基模拟的 Plk1 突变体 K209M 通过姐妹染色单体分离的能力丧失延长了中期到后期的持续时间。当细胞受到 DNA 损伤应激时，我们检测到 Plk1 K209me1 的积累。K209me1 的缺失会延迟 RPA2 和 RAD51 从 DNA 损伤部位的及时去除，表明 K209me1 在指导 DNA 损伤修复机制中的关键作用。因此，我们的研究强调了 Plk1 的甲基化-磷酸化开关在决定其激酶活性和在 DNA 损伤修复中的功能的重要性。
