CDK9-catalyzed phosphorylation of METTL3 promotes RNA polymerase II pause release and drives tumorigenesis

Description

CDK9-catalyzed phosphorylation of METTL3 promotes RNA polymerase II pause release and drives tumorigenesis: Precise control of RNA polymerase II (Pol II) pausing and release is essential for transcriptional regulation, yet how it is coordinated with oncogenic signaling and RNA modification remains unclear. Here, we identify CDK9-mediated phosphorylation of the m6A methyltransferase METTL3 as a key driver of Pol II pause release and oncogenic transcription. CDK9 extensively phosphorylates the intrinsically disordered N-terminal region of METTL3, promoting its incorporation into transcriptional condensates and its interactions with METTL14, Pol II and CDK9. This phosphorylation enables co-transcriptional m6A deposition and accelerates Pol II pause release, particularly at immediate early genes. Genetic or pharmacologic disruption of this CDK9-METTL3 phosphorylation impairs m6A deposition on mRNAs and chromatin-associated RNAs, delays transcriptional activation, and suppresses leukemogenesis in vitro and in vivo. Together, these findings define a CDK9-METTL3-m6A axis that mechanistically links kinase signaling to epitranscriptomic remodeling and transcriptional dynamics and reveal a therapeutically actionable vulnerability in m6A-dependent cancers.

Institutions

• City Of Hope National Medical Center

  California, Duarte

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