Mediator (coactivator)
The main function of mediator complexes is to transmit signals from the transcription factors to the polymerase.
The yeast Saccharomyces cerevisiae (a simple eukaryote) is thought to have up to 21 subunits in the core mediator (exclusive of the CDK module), while mammals have up to 26.
[3] A recent model showing the association of the polymerase with mediator in the absence of DNA is shown in the figure to the left.
[4] In addition to RNA polymerase II, mediator must also associate with transcription factors and DNA.
The mediator functions as a coactivator and binds to the C-terminal domain of RNA polymerase II holoenzyme, acting as a bridge between this enzyme and transcription factors.
[3] Mediator can be divided into 4 main parts: The head, middle, tail, and the transiently associated CDK8 kinase module.
[3][d] The figure shows how the splines of the Med 14 subunit connect a large portion of the complex together while still allowing flexibility.
Another example of structural variability is seen in vertebrates, in which 3 paralogues of subunits of the cyclin-dependent kinase module have evolved by 3 independent gene duplication events followed by sequence divergence.
[11][f] These stable associations have also been shown to regulate gene expression in vivo, and are prevented by mutations in MED12 that produce the human disease FG syndrome.
[16] Mediator is involved in "looping" of chromatin, which brings distant regions of a chromosome into closer physical proximity.
[3] In addition to the looping of euchromatin, mediator appears to be involved in formation or maintenance of heterochromatin at centromeres and telomeres.
[17] In both human cells and Caenorhabditis elegans MED15 is involved in lipid homeostasis through the pathway involving SREBPs[18] In the model plant Arabidopsis thaliana the ortholog of MED15 is required for signaling by the plant hormone Salicylic acid,[19] while MED25 is required for the transcriptional activation of Hypoxia (environmental), jasmonate and shade signalling responses.
[3] A method employing very gentle cell lysis in yeast followed by co-immunoprecipitation with an antibody to a mediator subunit (Med 17) has confirmed almost all previously reported or predicted interactions and revealed many previously unsuspected specific interactions of various proteins with mediator.
[37][38] By investigating hypomorphic mutants (which can survive 2 days longer), it was found that placental defects were primarily lethal and that there were also defects in cardiac and hepatic development, but many other organs were normal[38] Conditional mutations can be produced in mice which affect only specific cells or tissues at specific times, so that the mouse can develop to adulthood and the adult phenotype can be studied.
