Structure and functions of the Mediator complex: A key regulator of RNA polymerase II transcription

In eukaryotic cells from yeast to humans, the multi‐subunit Mediator complex contributes to transcriptional regulation of RNA polymerase II (Pol II) by acting as a coregulator. The Mediator regulates multiple stages of transcription by interacting with gene‐specific transcription factors, Pol II, and factors that regulate Pol II initiation and elongation. Mediator also affects the activities of factors involved in mRNA processing and chromatin regulation. Because of its central role in transcription, Mediator modulates pathways linked to cell differentiation, cell growth, and tissue development. Metazoan Mediator is composed of over 30 subunits in organized into several modules. In metazoa, Mediator core, composed of head, middle, and tail modules, can interact with a dissociable subunit called MED26. When isolated from cells, a large fraction of MED26‐containing Mediator is associated with Pol II; however, it remains unclear whether or how MED26 contributes to the Mediator‐Pol II interaction. A second form of Mediator lacks MED26 and instead binds a dissociable kinase module containing one of two kinase‐cyclin pairs, CDK8/Cyclin C or CDK19/Cyclin C. Because kinase module interferes with binding of the Mediator core to Pol II, it was proposed that Mediator associated with kinase module might function as a repressive cofactor; however, more recent results from multiple labs supports the model that both MED26‐Mediator and kinase module‐associated Mediator contribute to gene activation. A major focus of our research is to understand how these two forms of Mediator are involved in transcription regulation. Ongoing experiments seek to explore mechanisms that regulate Mediator‐Pol II interactions. In particular, we wish to understand (i) how Mediator recognizes Pol II and how the Mediator‐Pol II interaction is maintained, (ii) how Mediator is released from Pol II after transcription initiation, and (iii) whether and how the kinase module and MED26 contribute to each of these processes. Support or Funding Information The Stowers Institute for Medical ResearchThe Helen Nelson Medical Research Fund at Greater Kansas City Community Foundation