The methyltransferase SETD6 regulates Mitotic progression through PLK1 methylation

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Lysine methylation, mediated by protein lysine methyltransferases (PKMTs), is crucial for intracellular signaling.
• The roles of PKMTs and nonhistone protein methylation in cell cycle regulation remain largely uncharacterized.

Purpose of the Study:

• To investigate the function of the PKMT SETD6 in cell cycle regulation.
• To elucidate the mechanism by which SETD6 influences mitotic progression through its substrate PLK1.

Main Methods:

• Proteomic screening to identify PKMT substrates.
• Cellular assays to assess cell cycle progression in SETD6-deficient cells.
• Biochemical analysis to determine SETD6 methylation sites on PLK1.

Main Results:

• SETD6 was identified as a methyltransferase for PLK1, a key mitotic regulator.
• SETD6-deficient cells exhibit accelerated progression through mitosis and cytokinesis.
• SETD6 directly methylates PLK1 at lysine residues K209 and K413.
• Unmethylated PLK1 (at K209/K413) shows increased kinase activity, leading to faster mitosis and proliferation.

Conclusions:

• SETD6 plays a critical role in regulating the pace of mitotic progression.
• SETD6-mediated methylation of PLK1 is essential for maintaining normal mitotic timing.
• This study reveals a novel regulatory pathway involving SETD6 and PLK1 in cell cycle control.