A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair
Weizhe Li, Hong-Yan Wang, Xiaolu Zhao, Hongguo Duan, Binghua Cheng, Yafei Liu, Mengjie Zhao, Wenjie Shu, Yuchao Mei, Zengqi Wen, Mingliang Tang, Lin Guo, Guohong Li, Qiang Chen, Xiaoqi Liu and Hai-Ning Du
Abstract
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.
附件下载：
A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair, Science Advances, 06 Mar 2019
Science Advances, 06 March, 2019， DOI: http://dx.doi.org/10.1126/sciadv.aau7566
A methylation-phosphorylation switch determines Plk1 kinase activity and function in DNA damage repair
Weizhe Li, Hong-Yan Wang, Xiaolu Zhao, Hongguo Duan, Binghua Cheng, Yafei Liu, Mengjie Zhao, Wenjie Shu, Yuchao Mei, Zengqi Wen, Mingliang Tang, Lin Guo, Guohong Li, Qiang Chen, Xiaoqi Liu and Hai-Ning Du
Abstract
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.
文章链接：https://advances.sciencemag.org/content/5/3/eaau7566