The Mediator of transcriptional regulation was first characterized in yeast and is the central coactivator that enables a response of RNA polymerase II (Pol II) to activators and repressors (Kelleher et al., 1990, Richter et al., 2020). As a multi-protein complex, Mediator connects DNA-binding TFs with RNA polymerase II (Pol II) and thus serves as a central hub to regulate diverse aspects of transcription. The overall structure of the Mediator complex involves three major modules (Head, Middle, and Tail). The head and middle modules interact with Pol II, while the tail module interacts with various transcription factors (Khan et al., 2022, Malik et al., 2020). The head module is composed of MED6, MED8, MED11, SRB4/MED17, SRB5/MED18, ROX3/MED19, SRB2/MED20 and SRB6/MED22. The mediator complex also associates transiently with a CDK8 kinase module (Hasan et al., 2020). The CDK8 module is conserved in all eukaryotes and consists of 4 proteins: CDK8, CYCLIN C (CYCC), MED12, and MED13.

MED6 is an essential for viability component of the head module of the yeast mediator complex. It is involved in bridging between the head and tail modules of mediator.  A mutation of MED6 in yeast abolished activation of transcription of 5 inducible promoters in vivo, but this mutation had no effect on uninduced transcription, transcription of constitutively expressed genes, or transcription by RNA polymerases I and III (Lee et al., 1997, Kim et al., 2018). MED6 specifically interacts with Srb4, and this interaction is a requirement for transcriptional regulation of the RNA pol II holoenzyme (Lee et al., 1998, Verger et al., 2019). More recently, the structure of the RNA polymerase II (Pol II) preinitiation complex (PIC) that associates with the general coactivator Mediator has been examined. Three peptide regions containing eleven of the 26 heptapeptide repeats of the flexible C-terminal repeat domain (CTD) of Pol II were examined in detail.  It was found that CTD peptide 1 binds between the Med6 shoulder and Med31 knob domains, whereas CTD peptide 2 forms additional contacts with Med4. The third CTD region (peptide 3) binds in the Mediator cradle and associates with the Mediator hook (Schilbach et al., 2023).

There are three MED6 homologs in maize.

A database of Mediator genes/proteins from many animal, fungal, and plant species can be freely accessed at  www.nipgr.ac.in/MedProDB (Bhardwaj et al., 2021)

Last updated June 2023 by John Gray

References:

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Malik N, Ranjan R, Parida SK, Agarwal P, Tyagi AK. Mediator subunit OsMED14_1 plays an important role in rice development. Plant J. 2020 Mar;101(6):1411-1429. doi: 10.1111/tpj.14605. Epub 2019 Dec 12. PMID: 31702850.

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Hasan ASMM, Vander Schoor JK, Hecht V, Weller JL. The CYCLIN-DEPENDENT KINASE Module of the Mediator Complex Promotes Flowering and Reproductive Development in Pea. Plant Physiol. 2020 Mar;182(3):1375-1386. doi: 10.1104/pp.19.01173. Epub 2020 Jan 21. PMID: 31964799; PMCID: PMC7054868.

Richter WF, Nayak S, Iwasa J, Taatjes DJ. The Mediator complex as a master regulator of transcription by RNA polymerase II. Nat Rev Mol Cell Biol. 2022 Nov;23(11):732-749. doi: 10.1038/s41580-022-00498-3. Epub 2022 Jun 20. PMID: 35725906; PMCID: PMC9207880.

Bhardwaj R, Thakur JK, Kumar S. MedProDB: A database of Mediator proteins. Comput Struct Biotechnol J. 2021 Jul 27;19:4165-4176. doi: 10.1016/j.csbj.2021.07.031. PMID: 34527190; PMCID: PMC8342855.