Structural Biochemistry, Transcription Regulation by Mediator

The Mediator complex in humans has roles in regulating RNA polymerase II's ability to express genes for proteins. Not much is known about how it works, because of the sheer size of Mediator, 26 sub units and 1.2MDa, and can change composition if the promoters are different. This makes it seem like Mediator has an infinite number of regulatory functions.
Studying Mediator is difficult, because it is a challenging process to isolate it from human cells. It is not very abundant and is found taking different forms in the body. Another reason is that bioinformatics cannot be used to study its function. There is no conclusive evidence for Mediator being in microbes, so it is currently assumed to be only in eukaryotes.

Mediator Control of Transcription Machinery

Mediator's first discovered function was activity in activator-dependent transcription. Researchers found that Mediator is a target of DNA-biding transcription factors. However, Mediator may also play a role in activator-independent transcription, because it can cause basal transcription (a type of activator-independent transcription). This suggest Mediator could have control over initiation of transcription. More evidence to support this is RNA pol II recruitment is enhanced and transcription complexes are stabilized at the promoter by Mediator. Mediator has been shown to interact with Pre-Elongation Complex (PEC), which is the transcription initiation machinery, through its large surface area that allows for multiple protein-protein interactions. Also Mediator acts as a frame for PEC assembly.

CDK8 Submodule

Strangely, Mediator can also block RNA pol II from working with PEC, with the help of cyclin-dependent kinase 8 (CDK8). CDK8 contains the proteins CDK8, MED12, MED13, and cyclin C. CDK8's effect was discovered by separating Mediators with CDK8 and Mediators without and seeing that CDK8 Mediator could not begin transcription. It does this by inhibiting Mediator's ability to bind RNA pol II C-terminal Domain and recruit RNA pol II to a pre-elongation complex. Another role of CDK8 is regulating serum response genes such as FOS, EGRI, EGR2, and EGR3. CDK8 helps regulate RNA pol II phosphorylation and elongation at these genes.

Mediator Gene-Selective Functions

Mediator is likely to have a role in all protein-coding genes. New research has shown that MED1, the largest Mediator subunit is generally targeted by nuclear receptors. MED1 is phophorylation by extracellular signal-regulated kinase (ERK), stabilizing MED1 in Mediator. When MED1 is phophorylated, it shows better ability to activate transcription.

References

The human Mediator complex: a versatile, genome-wide regulator
of transcription - Dylan J. Taatjes

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