The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, 84105 Be'er-Sheva, Israel;
The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, 84105 Be'er-Sheva, Israel.
Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1235-1240. doi: 10.1073/pnas.1804407116. Epub 2019 Jan 8.
Lysine methylation, catalyzed by protein lysine methyltransferases (PKMTs), is a key player in regulating intracellular signaling pathways. However, the role of PKMTs and the methylation of nonhistone proteins during the cell cycle are largely unexplored. In a recent proteomic screen, we identified that the PKMT SETD6 methylates PLK1-a key regulator of mitosis and highly expressed in tumor cells. In this study, we provide evidence that SETD6 is involved in cell cycle regulation. SETD6-deficient cells were observed to progress faster through the different mitotic steps toward the cytokinesis stage. Mechanistically, we found that during mitosis SETD6 binds and methylates PLK1 on two lysine residues: K209 and K413. Lack of methylation of these two residues results in increased kinase activity of PLK1, leading to accelerated mitosis and faster cellular proliferation, similarly to SETD6-deficient cells. Taken together, our findings reveal a role for SETD6 in regulating mitotic progression, suggesting a pathway through which SETD6 methylation activity contributes to normal mitotic pace.
赖氨酸甲基化，由蛋白赖氨酸甲基转移酶（PKMTs）催化，是调节细胞内信号通路的关键因素。然而，PKMTs 的作用以及细胞周期中非组蛋白的甲基化在很大程度上尚未被探索。在最近的蛋白质组学筛选中，我们发现 PKMT SETD6 甲基化 PLK1-有丝分裂的关键调节因子，在肿瘤细胞中高度表达。在这项研究中，我们提供了 SETD6 参与细胞周期调控的证据。观察到 SETD6 缺陷细胞在有丝分裂的不同阶段更快地向胞质分裂阶段前进。从机制上讲，我们发现，在有丝分裂期间，SETD6 结合并甲基化 PLK1 的两个赖氨酸残基：K209 和 K413。这两个残基的甲基化缺失导致 PLK1 的激酶活性增加，从而加速有丝分裂和更快的细胞增殖，与 SETD6 缺陷细胞相似。总之，我们的发现揭示了 SETD6 在调节有丝分裂进程中的作用，提示 SETD6 甲基化活性有助于正常有丝分裂速度的途径。
