MED26 explained

Symbol:	Med26 N-terminal domain
Med26
Pfam:	PF08711
Interpro:	IPR017923

Symbol:	Med26_M
Mediator subunit 26 Middle domain
Pfam:	PF15694

Symbol:	Med26_C
Mediator subunit 26 C-terminal domain
Pfam:	PF15693

Mediator of RNA polymerase II transcription subunit 26 is an enzyme that in humans is encoded by the MED26 gene.^{[1] [2]} It forms part of the Mediator complex.

The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors.^[2]

Activity

MED26 is a transcription elongation factor that increases the overall transcription rate of RNA polymerase II by reactivating transcription elongation complexes that have arrested transcription. It does this through recruiting ELL/EAF- and P-TEFb- containing complexes to promoters via a direct interaction with the N-terminal domain (NTD). The MED26 NTD also binds TFIID, and TFIID and elongation complexes interact with MED26 through overlapping binding sites.^[3] MED26 NTD may function as a molecular switch contributing to the transition of Pol II into productive elongation.

The three structural domains of TFIIS are conserved from yeast to human. The 80 or so N-terminal residues form a protein interaction domain containing a conserved motif, which has been called the LW motif because of the invariant leucine and tryptophan residues it contains. Although the N-terminal domain is not needed for transcriptional activity, a similar sequence has been identified in other transcription factors and proteins that are predominantly nuclear localized.^{[4] [5] [6]} Specific examples are listed below:

• MED26 (also known as CRSP70 and ARC70), a subunit of the Mediator complex, which is required for the activity of the enhancer-binding protein Sp1.
• Elongin A, a subunit of a transcription elongation factor previously known as SIII. It increases the rate of transcription by suppressing transient pausing of the elongation complex.
• PPP1R10, a nuclear regulatory subunit of protein phosphatase 1 that was previously known as p99, FB19 or PNUTS.
• PIBP, a small hypothetical protein that could be a phosphoinositide binding protein.
• IWS1, which is thought to function in both transcription initiation and elongation.^[7]
• TFIIS, which rescues RNA polymerase II from backtracked pause states.

The N-terminal domain of MED26 is a protein fold known as a TFIIS N-terminal domain (or TND). It is a compact five-helix bundle. The hydrophobic core residues of helices 2, 3, and 4 are well conserved among TFIIS domains, although helix 1 is less conserved.

Interactions

MED26 has been shown to interact with MED8,^[8] Cyclin-dependent kinase 8,^[8] POLR2A,^[8] MED12^[8] and MED28.^[8] It also acts synergistically to mediate the interaction between REST (a Kruppel-type zinc finger transcription factor that binds to a 21-bp RE1 silencing element present in over 900 human genes) and Mediator.^[9]

Further reading

• Näär AM, Beaurang PA, Zhou S, Abraham S, Solomon W, Tjian R . Composite co-activator ARC mediates chromatin-directed transcriptional activation . Nature . 398 . 6730 . 828–832 . April 1999 . 10235267 . 10.1038/19789 . 23646963 . 1999Natur.398..828N .
• Booth V, Koth CM, Edwards AM, Arrowsmith CH . Structure of a conserved domain common to the transcription factors TFIIS, elongin A, and CRSP70 . The Journal of Biological Chemistry . 275 . 40 . 31266–31268 . October 2000 . 10811649 . 10.1074/jbc.M002595200 . free .
• Näär AM, Taatjes DJ, Zhai W, Nogales E, Tjian R . Human CRSP interacts with RNA polymerase II CTD and adopts a specific CTD-bound conformation . Genes & Development . 16 . 11 . 1339–1344 . June 2002 . 12050112 . 186316 . 10.1101/gad.987602 .
• Sato S, Tomomori-Sato C, Banks CA, Parmely TJ, Sorokina I, Brower CS, Conaway RC, Conaway JW . 6 . A mammalian homolog of Drosophila melanogaster transcriptional coactivator intersex is a subunit of the mammalian Mediator complex . The Journal of Biological Chemistry . 278 . 50 . 49671–49674 . December 2003 . 14576168 . 10.1074/jbc.C300444200 . free .
• Tomomori-Sato C, Sato S, Parmely TJ, Banks CA, Sorokina I, Florens L, Zybailov B, Washburn MP, Brower CS, Conaway RC, Conaway JW . 6 . A mammalian mediator subunit that shares properties with Saccharomyces cerevisiae mediator subunit Cse2 . The Journal of Biological Chemistry . 279 . 7 . 5846–5851 . February 2004 . 14638676 . 10.1074/jbc.M312523200 . free .
• Mo X, Kowenz-Leutz E, Xu H, Leutz A . Ras induces mediator complex exchange on C/EBP beta . Molecular Cell . 13 . 2 . 241–250 . January 2004 . 14759369 . 10.1016/S1097-2765(03)00521-5 . free .
• Sato S, Tomomori-Sato C, Parmely TJ, Florens L, Zybailov B, Swanson SK, Banks CA, Jin J, Cai Y, Washburn MP, Conaway JW, Conaway RC . 6 . A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology . Molecular Cell . 14 . 5 . 685–691 . June 2004 . 15175163 . 10.1016/j.molcel.2004.05.006 . free .
• Zhang X, Krutchinsky A, Fukuda A, Chen W, Yamamura S, Chait BT, Roeder RG . MED1/TRAP220 exists predominantly in a TRAP/ Mediator subpopulation enriched in RNA polymerase II and is required for ER-mediated transcription . Molecular Cell . 19 . 1 . 89–100 . July 2005 . 15989967 . 10.1016/j.molcel.2005.05.015 . free .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–648 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .

Notes and References

1. Ryu S, Zhou S, Ladurner AG, Tjian R . The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1 . Nature . 397 . 6718 . 446–450 . February 1999 . 9989412 . 10.1038/17141 . free . 4405569 . 1999Natur.397..446R . 11858/00-001M-0000-0019-A36A-8 .
2. Web site: Entrez Gene: CRSP7 cofactor required for Sp1 transcriptional activation, subunit 7, 70kDa.
3. Takahashi H, Parmely TJ, Sato S, Tomomori-Sato C, Banks CA, Kong SE, Szutorisz H, Swanson SK, Martin-Brown S, Washburn MP, Florens L, Seidel CW, Lin C, Smith ER, Shilatifard A, Conaway RC, Conaway JW . 6 . Human mediator subunit MED26 functions as a docking site for transcription elongation factors . Cell . 146 . 1 . 92–104 . July 2011 . 21729782 . 3145325 . 10.1016/j.cell.2011.06.005 .
4. Cermakova K, Veverka V, Hodges HC . The TFIIS N-terminal domain (TND): a transcription assembly module at the interface of order and disorder . Biochemical Society Transactions . 125–135 . January 2023 . 51 . 1 . 36651856 . 10.1042/BST20220342 . 255969299 . 9987994 .
5. Booth V, Koth CM, Edwards AM, Arrowsmith CH . Structure of a conserved domain common to the transcription factors TFIIS, elongin A, and CRSP70 . The Journal of Biological Chemistry . 275 . 40 . 31266–31268 . October 2000 . 10811649 . 10.1074/jbc.M002595200 . free .
6. Ling Y, Smith AJ, Morgan GT . A sequence motif conserved in diverse nuclear proteins identifies a protein interaction domain utilised for nuclear targeting by human TFIIS . Nucleic Acids Research . 34 . 8 . 2219–2229 . 2006 . 16648364 . 1450333 . 10.1093/nar/gkl239 .
7. Cermakova K, Demeulemeester J, Lux V, Nedomova M, Goldman SR, Smith EA, Srb P, Hexnerova R, Fabry M, Madlikova M, Horejsi M, De Rijck J, Debyser Z, Adelman K, Hodges HC, Veverka V . 6 . A ubiquitous disordered protein interaction module orchestrates transcription elongation . Science . 374 . 6571 . 1113–1121 . November 2021 . 34822292 . 8943916 . 10.1126/science.abe2913 . 2021Sci...374.1113C .
8. Sato S, Tomomori-Sato C, Parmely TJ, Florens L, Zybailov B, Swanson SK, Banks CA, Jin J, Cai Y, Washburn MP, Conaway JW, Conaway RC . 6 . A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology . Molecular Cell . 14 . 5 . 685–691 . June 2004 . 15175163 . 10.1016/j.molcel.2004.05.006 . free .
9. Ding N, Tomomori-Sato C, Sato S, Conaway RC, Conaway JW, Boyer TG . MED19 and MED26 are synergistic functional targets of the RE1 silencing transcription factor in epigenetic silencing of neuronal gene expression . The Journal of Biological Chemistry . 284 . 5 . 2648–2656 . January 2009 . 19049968 . 2631966 . 10.1074/jbc.M806514200 . free .