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Regulatory functions of the Mediator kinases CDK8 and CDK19
Charli B Fant1, Dylan J Taatjes1
1a Department of Biochemistry , University of Colorado , Boulder , CO , USA.
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.
Insights
Mediator kinases CDK8 and CDK19 regulate gene transcription by phosphorylating factors and influencing Mediator structure. These kinases play roles in cellular reprogramming and have therapeutic potential.
Area of Science:
- Molecular Biology
- Gene Regulation
- Biochemistry
Background:
- The Mediator complex is crucial for regulating gene transcription by RNA polymerase II (pol II).
- CDK8 and CDK19 are core components of the Mediator kinase module, influencing its function.
- CCNC, MED12, and MED13 proteins are essential for CDK8/CDK19 activity and Mediator association.
Purpose of the Study:
- To review the cellular roles and regulatory mechanisms of Mediator kinases CDK8 and CDK19.
- To explore how these kinases mediate transcriptional reprogramming through transcription factors and chromatin structure.
- To summarize current knowledge on Mediator kinase inhibitors and their therapeutic applications.
Main Methods:
- This review synthesizes existing research on Mediator kinases.
- Focuses on mechanisms involving transcription factors, DNA-binding proteins, and chromatin looping.
- Compares conserved and divergent functions between yeast and mammalian CDK8.
Main Results:
- Mediator kinases indirectly affect pol II transcription via phosphorylation of transcription factors.
- CDK8/CDK19 influence Mediator structure and function, impacting gene expression.
- These kinases are implicated in metabolic and transcriptional reprogramming via enhancers and chromatin looping.
Conclusions:
- Mediator kinases CDK8 and CDK19 are key regulators of gene transcription with significant cellular roles.
- Further research is needed to elucidate enigmatic functions, including roles in pol II pausing and phase separation.
- Mediator kinase inhibitors show therapeutic potential for various diseases.
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