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

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 Funding information This work was supported by: NIGMS NIH HHS, United States Grant ID: R01 GM063873 NIGMS NIH HHS, United States Grant ID: R01 GM056985 NIBIB NIH HHS, United States Grant ID: R01 EB001987 Howard Hughes Medical Institute, United States NIGMS NIH HHS, United States Grant ID: GM056985 NIBIB NIH HHS, United States Grant ID: EB001987 NIGMS NIH HHS, United States Grant ID: GM063873 More Less keyboard_arrow_down