Cdk7: a kinase at the core of transcription and in the crosshairs of cancer drug discovery

Abstract

The transcription cycle of RNA polymerase II (Pol II) is regulated by a set of cyclin-dependent kinases (CDKs). Cdk7, associated with the transcription initiation factor TFIIH, is both an effector CDK that phosphorylates Pol II and other targets within the transcriptional machinery, and a CDK-activating kinase (CAK) for at least one other essential CDK involved in transcription. Recent studies have illuminated Cdk7 functions that are executed throughout the Pol II transcription cycle, from promoter clearance and promoter-proximal pausing, to co-transcriptional chromatin modification in gene bodies, to mRNA 3´-end formation and termination. Cdk7 has also emerged as a target of small-molecule inhibitors that show promise in the treatment of cancer and inflammation. The challenges now are to identify the relevant targets of Cdk7 at each step of the transcription cycle, and to understand how heightened dependence on an essential CDK emerges in cancer, and might be exploited therapeutically.

Keywords: Cdk7; RNA polymerase II; cancer drug discovery; mRNA-capping; promoter-proximal pausing.

Figure 1.

Cdk7 functions during the Pol II transcription cycle. Cdk7 acts at multiple points during progression through the Pol II transcription cycle. These functions can be direct effects of Cdk7-mediated phosphorylation, for example, of the CTD on Ser5 and Ser7 positions (only pSer5 is shown for clarity) to dissolve Pol II clusters and allow entry into transcription. Later in the cycle, Cdk7 works through unknown targets to implement a promoter-proximal pause (dashed line) and indirectly, through activation of Cdk9/cyclin T1 (P-TEFb), to release the pause. Later events are mediated by Cdk12/and Cdk13/cyclin K, which might also be targets of the CAK function of Cdk7 (gray arrow).

Figure 2.

An early checkpoint in transcription. Cdk7, together with regulatory subunits cyclin H and Mat1, is part of the general transcription factor (GTF) TFIIH that assembles into the preinitiation complex (PIC) at Pol II promoters. Another GTF in the PIC, TFIIE, binds the clamp region of Pol II (top panel). Between initiation and the promoter-proximal pause. Cdk7 acts by an unknown exchange mechanism to promote displacement of TFIIE and recruitment to the Pol II clamp of DSIF, which, together with NELF, establishes the pause. Concomitant with pausing, Cdk7 phosphorylates the Pol II CTD to tether the mammalian capping enzyme (MCE) in proximity to the 5´-triphosphate end of the nascent RNA transcript (middle panel). Cdk7 is the activating kinase for Cdk9/cyclin T1 (P-TEFb), which phosphorylates DSIF (converting it to a positive elongation factor), NELF (which dissociates) and Pol II, to trigger pause release and rapid elongation of the 5´-capped transcript (bottom panel).