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Review
. 2019 Apr;10(2):76-90.
doi: 10.1080/21541264.2018.1556915. Epub 2018 Dec 26.

Regulatory functions of the Mediator kinases CDK8 and CDK19

Charli B Fant  1 , Dylan J Taatjes  1
Affiliations
Review

Regulatory functions of the Mediator kinases CDK8 and CDK19

Charli B Fant et al. Transcription. 2019 Apr.

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.

Keywords: Mediator kinase; RNA polymerase II; chromatin; enhancer; transcription.

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Figures

Figure 1.
Figure 1.
Speculative models for CDK8 or CDK19 module function at mammalian enhancers. a) CDK8 or CDK19 module (“K”) association with an enhancer (e.g. via TF binding) enables its interaction with promoters that are juxtaposed via chromatin loops. This co-localization may be facilitated by liquid-liquid phase separation (LLPS)[137], which is represented by grey shading. At gene A (left), CDK8/19 module–Mediator binding occurs after pol II clears the promoter. Whereas this interaction prevents rapid re-initiation by another pol II complex, promoter-bound CDK8-Mediator can regulate pol II pausing and/or elongation, through physical or functional interactions with the Super-Elongation Complex (SEC) or other factors [17,62]. At gene B (right), transcriptional bursting is depicted[137], in which multiple pol II complexes initiate in succession[70]. This process appears to be Mediator-dependent[148]. The CDK8/19 module does not associate with Mediator at this promoter, as CDK8 module–Mediator binding is mutually exclusive with Mediator–pol II binding [146,147]. Note that at a different point in time, the situation could be switched, with CDK8/19 module association with gene B and gene A undergoing transcriptional bursting. b) An alternative model enables the CDK8/19 module to function independently of Mediator[117]; the enhancer-bound kinase module may regulate transcription elongation via its juxtaposition with elongating pol II complexes at co-localized genes. In support of this model, enhancers have been observed to track with elongating pol II[149], and the CDK8 module appears to positively regulate transcription elongation[17].
Figure 2.
Figure 2.
Summary of intrinsically disordered regions (IDRs) in kinase module subunits. a) Comparison of yeast (S. cerevisiae) Med12 and Med13 with human MED12 and MED13. Overall sequence identity is about 13% for yeast vs. human MED12 and MED13. b) Comparison of human MED12, MED12L and human MED13, MED13L. Not shown are CDK8, CDK19, and CCNC, which are largely structured, but each contains IDRs at their C-termini. Plots were generated with IUPred2A[152]; regions with values over 0.5 are considered disordered.
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