METTL3 promotes cell-cycle progression via activation of transcriptional elongation.
TL;DR
This work identifies the m6A methyltransferase METTL3 as a direct substrate of the mitotic kinase CDK1 in mammalian cells and reveals a mechanism by which transcriptional elongation is coordinated with chromosome segregation fidelity.
Abstract
Transcriptional elongation undergoes extensive remodeling at mitotic entry, yet how elongation control is integrated into core cell-cycle kinase networks remains unclear. Here, we identify the m6A methyltransferase METTL3 as a direct substrate of the mitotic kinase CDK1 in mammalian cells. CDK1-dependent phosphorylation of METTL3 at Ser43 is sharply induced at mitotic entry and promotes m6A methylation of the noncoding RNA 7SK, resulting in release of positive transcription elongation factor b (P-TEFb) from the inhibitory 7SK small nuclear ribonucleoprotein particle (snRNP) complex. This activation of the m6A/7SK/P-TEFb axis facilitates genome-wide clearance of RNA polymerase II and supports timely mitotic progression. Endogenous mutation of METTL3 Ser43 or disruption of 7SK methylation impairs elongation dynamics, delays mitotic exit, and increases chromosome missegregation. These findings integrate RNA methylation into the CDK1-driven mitotic program and reveal a mechanism by which transcriptional elongation is coordinated with chromosome segregation fidelity.