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

Stéphane Larochelle, Ramon Amat, Kira Glover-Cutter, Miriam Sansó, Chao Zhang, Jasmina J. Allen, Kevan M. Shokat, David L. Bentley, Robert P. Fisher

Research output: Contribution to journalArticlepeer-review

296 Scopus citations

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.

Original languageEnglish
Pages (from-to)1108-1115
Number of pages8
JournalNature Structural and Molecular Biology
Volume19
Issue number11
DOIs
StatePublished - Nov 2012

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