METTL3 promotes cell-cycle progression via activation of transcriptional elongation

Abstract Transcription elongation through the phosphorylation of RNA Pol II by CDK9 (P-TEFb) is not only required for mRNA transcription to produce proteins, but is a fundamental mechanism required for proper cell cycle progression. N6-methyladenosine (m 6 A) methyltransferase METTL3 methylates mRNAs co-transcriptionally, modulating their downstream processing as well as the non-coding RNA 7SK post-transcriptionally. We found that CDK1 phosphorylates METTL3 at Ser43 at the onset of mitosis. This METTL3 phosphorylation promotes transcriptional elongation via the m 6 A/7SK/P-TEFb axis, allowing RNA Pol II clearance and proper cell cycle progression. Disruption of this pathway results in defects in chromosome segregation. Our findings establish a novel mechanistic link between CDK1 regulation of transcriptional elongation through activation of METTL3 and RNA methylation.