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July 17th, 2025
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Yale University
molecular biology
biorxiv

METTL3 promotes cell cycle progression via activation of transcriptional elongation.

Alarcon, C.Open in Google Scholar

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 (m6A) 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 m6A/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.

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