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Nat Struct Mol Biol. 2012 Nov;19(11):1108-15. doi: 10.1038/nsmb.2399. Epub 2012 Oct 14.

Cyclin-dependent kinase control of the initiation-to-elongation switch of RNA polymerase II.

Author information

1
Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York, USA.

Abstract

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.

PMID:
23064645
PMCID:
PMC3746743
DOI:
10.1038/nsmb.2399
[Indexed for MEDLINE]
Free PMC Article

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