Figure 2.

CDK9 is a central hub for proper signaling of each step in the transcription cycle. (a) CDK9 phosphorylation signals for Pol II pause release and initiation. Pausing of Pol II is facilitated by the negative elongation factors, DSIF and NELF (top) and blocks initiation of new Pol II molecules. Upon transcription stimulation, CDK9 phosphorylates the negative elongation factors and Ser2 of the Pol II CTD at promoters resulting in the removal of elongation blocks, release of Pol II into elongation, and initiation of new Pol II molecules (bottom). Inhibition of CDK9 (CDK9i) prohibits release of Pol II into elongation thereby blocking new polymerases from initiating (right). b) CDK9 is critical for proper transcription termination. Pol II pauses at poly(A) sites allowing for the CDK9-dependent phosphorylation of the Pol II CTD and recruitment of termination factors. CTD phosphorylation then provides a platform for the recruitment of termination factors at poly(A) sites and pause-release for proper termination and 3ʹ-end formation. CDK9 also phosphorylates a regulatory subunit of the PP1 phosphatase, preventing dephosphorylation of DSIF and premature termination. Once released from its paused state, Pol II transcribes through the poly(A) site resulting in the activation of PP1, dephosphorylation of DSIF, and transcription termination. CDK9 inhibitor (CDK9i) studies found that inhibition of CDK9 decreases transcript levels downstream of the poly(A) site resulting in a termination defect (right). Note that the different Pol II forms (initiating, pausing, elongating, and terminating) are color-coded for ease visualization.