Regulatory functions of the Mediator kinases CDK8 and CDK19

Abstract

The Mediator-associated kinases CDK8 and CDK19 function in the context of three additional proteins: CCNC and MED12, which activate CDK8/CDK19 kinase function, and MED13, which enables their association with the Mediator complex. The Mediator kinases affect RNA polymerase II (pol II) transcription indirectly, through phosphorylation of transcription factors and by controlling Mediator structure and function. In this review, we discuss cellular roles of the Mediator kinases and mechanisms that enable their biological functions. We focus on sequence-specific, DNA-binding transcription factors and other Mediator kinase substrates, and how CDK8 or CDK19 may enable metabolic and transcriptional reprogramming through enhancers and chromatin looping. We also summarize Mediator kinase inhibitors and their therapeutic potential. Throughout, we note conserved and divergent functions between yeast and mammalian CDK8, and highlight many aspects of kinase module function that remain enigmatic, ranging from potential roles in pol II promoter-proximal pausing to liquid-liquid phase separation.

Structure and mechanism of the RNA polymerase II transcription machinery

“…The Mediator kinase module is a large complex (600 kDa; Table 1) that contains four subunits (Fant and Taatjes 2019). In the yeast S. cerevisiae, the kinase module consists of Srb8-11, which are orthologs of the human genes MED12, MED13, CDK8, and CCNC.…”

Enhancer architecture sensitizes cell specific responses to Notch gene dose via a bind and discard mechanism

“…The CKM has a complex relationship with promoter transcription (Fant and Taatjes, 2019). Some studies suggest interactions between the CKM and the core Mediator occludes RNA polymerase recruitment (Knuesel, et al, 2009a) and/or decreases transcription (Pelish, et al, 2015), whereas other studies suggest Cdk8 stimulates transcription (Galbraith, et al, 2013;Donner, et al, 2010).…”

Manipulating the Mediator complex to induce naïve pluripotency

“…The Mediator tail-domain interacts with the enhancer chromatin, including transcription factors and cofactors, while the middle- and head-domains form contacts with RNA Pol II and the pre-initiation complex at target promoters [ 8 , 18 , 19 ]. While the many subunits of Mediator can undergo extensive structural re-arrangements, the CDK8/19-module contains the only enzymatic activity of Mediator, namely the kinase CDK8 or its highly similar, but poorly studied, paralog CDK19 [ 9 , 21 , 22 ]. Completing the kinase module are: cyclin C (CCNC), and subunits MED12 and MED13.…”

“…For full activity, CDK8/19 must associate simultaneously with cyclin C and with MED12, the latter embraces CDK8 allowing it to attain proper opening of its T-loop [ 23 ]. Evidence suggests that only CDK8, or CDK19, can occupy Mediator at one time, and the same is true for the paralog subunits MED12L and MED13L (reviewed elsewhere) [ 8 , 9 , 22 ]. Collectively, these may represent alternate combinations of the CDK8/19-module, providing opportunity for subtle modulation of Mediator function.…”