The methyltransferase SETD6 regulates Mitotic progression through PLK1 methylation

Abstract

Significance The involvement of nonhistone protein methylation in cellular essential pathways is a rising field. Here we show evidence for the involvement of direct lysine methylation of the mitosis regulator PLK1 by SETD6 methyltransferase in cell cycle promotion. Our results reveal that this methylation occurs on two lysine residues and that lack of methylation leads to enhanced PLK1 catalytic activity, causing accelerated mitosis pace and thus faster proliferation rates. These findings suggest that PLK1 methylation by SETD6 controls the pace of mitotic progression, greatly enhancing our understanding of cell cycle complexity. The role of methylation in mitotic progression raises the possibility of its involvement in tumorigenic pathways by orchestrating cell division rates and might have insightful implications for the development of cancer-specific markers. 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.