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

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.

Pubmed ID: 23064645


  • Larochelle S
  • Amat R
  • Glover-Cutter K
  • Sansó M
  • Zhang C
  • Allen JJ
  • Shokat KM
  • Bentley DL
  • Fisher RP


Nature structural & molecular biology

Publication Data

November 7, 2012

Associated Grants

  • Agency: NIBIB NIH HHS, Id: EB001987
  • Agency: NIGMS NIH HHS, Id: GM056985
  • Agency: NIGMS NIH HHS, Id: GM063873
  • Agency: NIBIB NIH HHS, Id: R01 EB001987
  • Agency: NIGMS NIH HHS, Id: R01 GM056985
  • Agency: NIGMS NIH HHS, Id: R01 GM063873
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Chromatin Immunoprecipitation
  • Cyclin-Dependent Kinase 9
  • Cyclin-Dependent Kinases
  • HCT116 Cells
  • Histones
  • Humans
  • Immunoblotting
  • Nuclear Proteins
  • Phosphorylation
  • RNA Polymerase II
  • Transcription Elongation, Genetic
  • Transcription Factors
  • Transcription Factors, TFII
  • Transcription Initiation, Genetic
  • Transcriptional Elongation Factors
  • Ubiquitination