A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair
A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair
复制标题
甲基化-磷酸化开关决定 Plk1 激酶活性和 DNA 损伤修复功能
DOI：
10.1126/sciadv.aau7566
复制
发表时间：
2019-03-01
期刊：
影响因子：
13.6
通讯作者：
Du, Hai-Ning
中科院分区：
文献类型：
--
作者：
Li, Weizhe;Wang, Hong-Yan;Du, Hai-Ning
Polo样激酶1（Plk 1）是细胞周期进程的重要调节因子，但Plk 1活性的调节机制尚不清楚。我们目前的证据表明，Plk 1活性是由一个平衡的甲基化和磷酸化开关控制。甲基转移酶G9 a在Lys 209处使Plk 1单甲基化，其拮抗T210的磷酸化以抑制Plk 1活性。我们发现，甲基缺陷型Plk 1突变体K209 A影响DNA复制，而甲基模拟型Plk 1突变体K209 M通过不能分离姐妹染色单体来抑制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Plk 1 K209 me 1的积累。K209 me 1的消融延迟了RPA 2和RAD 51从DNA损伤位点的及时去除，表明K209 me 1在引导DNA损伤修复机制中的关键作用。因此，我们的研究强调了Plk 1的甲基化-磷酸化开关在决定其激酶活性和DNA损伤修复功能方面的重要性。
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.