Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 19, Issue 11, Pages 1108-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2399
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Funding
- Beatriu de Pinos fellowship of the Generalitat de Catalunya
- US National Institutes of Health [GM056985, GM063873, EB001987]
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Promoter-proximal pausing by RNA polymerase II (Pol II) ensures gene-specific regulation and RNA quality control. Structural considerations suggested a requirement for initiation-factor eviction in elongation-factor engagement and pausing of transcription complexes. Here we show that selective inhibition of Cdk7-part of TFIIH-increases TFIIE retention, prevents DRB sensitivity-inducing factor (DSIF) recruitment and attenuates pausing in human cells. Pause release depends on Cdk9-cyclin T1 (P-TEFb); Cdk7 is also required for Cdk9-activating phosphorylation and Cdk9-dependent downstream events-Pol II C-terminal domain Ser2 phosphorylation and histone H2B ubiquitylation-in vivo. Cdk7 inhibition, moreover, impairs Pol II transcript 3'-end formation. Cdk7 thus acts through TFIIE and DSIF to establish, and through P-TEFb to relieve, barriers to elongation: incoherent feedforward that might create a window to recruit RNA-processing machinery. Therefore, cyclin-dependent kinases govern Pol II handoff from initiation to elongation factors and cotranscriptional RNA maturation.
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