Mediator (coactivator)

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Diagram of mediator with cyclin-dependent kinase module Mediator4TC.jpg
Diagram of mediator with cyclin-dependent kinase module

Mediator is a multiprotein complex that functions as a transcriptional coactivator in all eukaryotes. It was discovered in 1990 in the lab of Roger D. Kornberg, recipient of the 2006 Nobel Prize in Chemistry. [1] [2] Mediator [lower-alpha 1] complexes interact with transcription factors and RNA polymerase II. The main function of mediator complexes is to transmit signals from the transcription factors to the polymerase. [3]

Contents

Mediator complexes are variable at the evolutionary, compositional and conformational levels. [3] The first image shows only one "snapshot" of what a particular mediator complex might be composed of, [lower-alpha 2] but it certainly does not accurately depict the conformation of the complex in vivo. During evolution, mediator has become more complex. 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.

Individual subunits can be absent or replaced by other subunits under different conditions. Also, there are many intrinsically disordered regions in mediator proteins, which may contribute to the conformational flexibility seen both with and without other bound proteins or protein complexes. A more realistic model of a mediator complex without the CDK module is shown in the second figure. [4]

The mediator complex is required for the successful transcription by RNA polymerase II. Mediator has been shown to make contacts with the polymerase in the transcription preinitiation complex. [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. A model of such interactions is shown in the figure to the right. [5] Note that the different morphologies of mediator do not necessarily mean that one of the models is correct; rather those differences may reflect the flexibility of mediator as it interacts with other molecules. [lower-alpha 3] For example, after binding the enhancer and core promoter, the mediator complex undergoes a compositional change in which the kinase module dissociates from the complex to allow association with RNA polymerase II and transcriptional activation. [6]

The Mediator complex is located within the cell nucleus. It is required for the successful transcription of nearly all class II gene promoters in yeast. [7] It works in the same manner in mammals. 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. [8]

Structure

Mediator complex architecture with focus on the disordered "spline" of Med 14 MediatorSpline4TC.jpg
Mediator complex architecture with focus on the disordered "spline" of Med 14

The yeast mediator complex is approximately as massive as a small subunit of a eukaryotic ribosome. The yeast mediator is composed of 25 subunits, while the mammalian mediator complexes are slightly larger. [3] Mediator can be divided into 4 main parts: The head, middle, tail, and the transiently associated CDK8 kinase module. [10]

Mediator subunits have many intrinsically disordered regions called "splines", which may be important to allow the structural changes of the mediator that change the function of the complex. [3] [lower-alpha 4] The figure shows how the splines of the Med 14 subunit connect a large portion of the complex together while still allowing flexibility. [4] [lower-alpha 5]

Mediator complexes that lack a subunit have been found or produced. These smaller mediators can still function normally in some activity, but lack other capabilities. [3] This indicates a somewhat independent function of some of the subunits while being part of the larger complex.

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. [3]

Mediator structural model MediatorStrucMod4TC.jpg
Mediator structural model

There is a report that mediator forms stable associations with a particular type of non-coding RNA, ncRNA-a. [11] [lower-alpha 6] 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. [11] Thus, the structure of a mediator complex can be augmented by RNA as well as proteinaceous transcription factors. [3]

Function

Structural model of the tail and middle of mediator bound to RNA polymerase II MediatorPolII4TC.jpg
Structural model of the tail and middle of mediator bound to RNA polymerase II

Mediator was originally discovered because it was important for RNA polymerase II function, but it has many more functions than just interactions at the transcription start site. [3]

RNA polymerase II-Mediator core initiation complex

Mediator is a crucial component for transcription initiation. Mediator interacts with the pre-initiation complex, composed of RNA Polymerase II and general transcription factors TFIIB, TFIID, TFIIE, TFIIF, and TFIIH to stabilize and initiate transcription. [12] Studies of Mediator-RNA Pol II contacts in budding yeast have emphasized the importance of TFIIB-Mediator contacts in the formation of the complex. Interactions of Mediator with TFIID in the initiation complex has been shown. [10]

The Structure of a core Mediator (cMed) that's associated with a core pre-initiation complex was elucidated. [12]

RNA synthesis

The preinitiation complex, which contains a mediator, transcription factors, a nucleosome [13] [14] [lower-alpha 7] and RNA polymerase II, is important to position the polymerase for the start of transcription. Before RNA synthesis can occur, the polymerase must dissociate from mediator. This appears to be accomplished by phosphorylation of part of the polymerase by a kinase. Importantly, mediator and transcription factors do not dissociate from the DNA at the time polymerase begins transcription. Rather, the complex remains at the promoter to recruit another RNA polymerase to begin another round of transcription. [3] [lower-alpha 8]

There is some evidence to suggest that mediator in a yeast is involved in regulating RNA polymerase III (Pol III) transcripts of tRNAs [15] In support of that evidence, an independent report showed specific association of mediator with Pol III in Saccharomyces cerevisiae. [16] Those authors also reported specific associations with RNA polymerase I and proteins involved in transcription elongation and RNA processing, supporting other evidence of mediator's involvement in elongation and processing. [16]

Chromatin organization

Mediator is involved in "looping" of chromatin, which brings distant regions of a chromosome into closer physical proximity. [3] The ncRNA-a mentioned above [11] is involved in such looping. [lower-alpha 9] Enhancer RNAs (eRNAs) can function similarly. [3]

In addition to the looping of euchromatin, mediator appears to be involved in formation or maintenance of heterochromatin at centromeres and telomeres. [3]

Signal transduction

TGFβ signaling at the cell membrane results in 2 different intracellular pathways. One of them depends on MED15, [lower-alpha 10] while the other is independent of MED15. [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 jasmonate and shade signalling responses. [20] [21] [22] Two components of the CDK module (MED12 and MED13) are involved in the Wnt signaling pathway [3] MED23 is involved in RAS/MAPK/ERK pathway [3] This abbreviated review shows the versatility of individual mediator subunits, and leads to the idea that mediator is an end-point of signaling pathways. [3]

Human disease

Involvement of mediator in various human diseases has been reviewed. [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] Since inhibiting one interaction of a disease-causing signaling pathway with a subunit of mediator may not inhibit general transcription needed for normal function, mediator subunits are attractive candidates for therapeutic drugs. [3]

Interactions

Mediator interactome in Saccharomyces cerevisiae MediatorInteract4TC.jpg
Mediator interactome in Saccharomyces cerevisiae

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. [16]

MED 1

The interaction network of MED1 protein from BioPlex 2.0 BioPlexMed1c.jpg
The interaction network of MED1 protein from BioPlex 2.0

A discussion of all mediator subunits is beyond the scope of this article, but details of one of the subunits are illustrative of the types of information that may be gathered for other subunits.

regulation by Micro RNAs

Micro RNAs are involved in regulating the expression of many proteins. Med1 is targeted by miR-1, which is important in gene regulation in cancers. [34] The tumor suppressor miR-137 also regulates MED1. [35]

Mouse embryonic development

Null mutants die at an early gestational age (embryonic day 11.5). [36] [37] 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 [37]

Mouse cells and tissues

A mediator mutation causes hairy teeth in mice HairyTeeth4TC.jpg
A mediator mutation causes hairy teeth in mice

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. In one case, MED1 was found to participate in controlling the timing of events of meiosis in male mice. [38] Conditional mutants in keratinocytes show differences in skin wound healing. [39] A conditional mutant in mice was found to change dental epithelium into epidermal epithelium, which caused hair to grow associated with the incisors. [40]

Subunit composition

The Mediator complex is composed at least 31 subunits in all eukaryotes studied: MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED28, MED29, MED30, MED31, CCNC, and CDK8. There are three fungal-specific components, referred to as Med2, Med3 and Med5. [41]

The subunits form at least three structurally distinct submodules. The head and the middle modules interact directly with RNA polymerase II, whereas the elongated tail module interacts with gene-specific regulatory proteins. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation.

In other species

Below is a cross-species comparison of mediator complex subunits. [41] [42]

Subunit No. Human gene C. elegans gene D. melanogaster gene S. cerevisiae gene Sch. pombe gene
MED1 MED1Sop3/mdt-1.1, 1.2MED1MED1med1
Med2 [lower-alpha 11] MED2
Med3 [lower-alpha 11] PGD1
MED4 MED4MED4MED4med4
Med5 [lower-alpha 11] NUT1
MED6 MED6MDT-6MED6MED6med6
MED7 MED7MDT-7/let-49MED7MED7med7
MED8 MED8MDT-8MED8MED8med8
MED9 MED9MED9CSE2
MED10 MED10MDT-10NUT2med10
MED11 MED11MDT-11MED11MED11med11
MED12 MED12MDT-12/dpy-22MED12SRB8srb8
MED12L MED12L
MED13 MED13MDT-13/let-19MED13SSN2srb9
MED14 MED14MDT-14/rgr-1MED14RGR1med14
MED15 MED15mdt-15MED15GAL11YN91_SCHPO [lower-alpha 12]
MED16 MED16MED16SIN4
MED17 MED17MDT-17MED17SRB4med17
MED18 MED18MDT-18MED18SRB5med18
MED19 MED19MDT-19MED19ROX3 [41] med19
MED20 MED20MDT-20MED20SRB2med20
MED21 MED21MDT-21MED21SRB7med21
MED22 MED22MDT-22MED22SRB6med22
MED23 MED23MDT-23/sur-2MED23
MED24 MED24MED24
MED25 MED25MED25
MED26 MED26MED26
MED27 MED27MED27med27
MED28 MED28MED28
MED29 MED29MDT-19MED29
MED30 MED30MED30
MED31 MED31MDT-31MED31SOH1med31
CCNC CCNC cic-1CycCSSN8pch1
CDK8 CDK8cdk-8Cdk8SSN3srb10

Notes

  1. ↑ Mediator is also referred to in scientific literature as the vitamin D receptor interacting protein (DRIP) coactivator complex and the thyroid hormone receptor-associated proteins (TRAP).
  2. ↑ However note that more recently it has been found that the CDK module and MED26 cannot be present concurrently in a complex. [3]
  3. ↑ The sharp bend in the DNA associated with the transcription bubble is shown in the graphical abstract and first figure of this research paper
  4. ↑ Some of those changes are diagrammed in figure 1 of the review article, which can be viewed in slightly larger form by clicking it at that site.
  5. ↑ Note that Med 17 (shown in blue) also has that sort of spline
  6. ↑ These non-coding activating RNAs have not been mentioned yet in the ncRNA article as of 16 February 2017
  7. ↑ This is the +1 nucleosome, which "covers" the transcription start site during the preinitiation phase.
  8. ↑ This is diagrammed in figure 2 of the review article, which can be viewed in slightly larger form by clicking it at that site.
  9. ↑ This is diagrammed in figure 3 of the review article, which can be viewed in slightly larger form by clicking it at that site. That figure also shows Pol II disengaged from mediator, etc, which remains on the DNA
  10. ↑ Also known as ARC105 in Xenopus laevis, the model species in which the work was done.
  11. 1 2 3 Fungal-specific
  12. ↑ Protein-name in Sch. pombe

Related Research Articles

<span class="mw-page-title-main">RNA polymerase II</span> Protein complex that transcribes DNA

RNA polymerase II is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryotic cells. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase. A wide range of transcription factors are required for it to bind to upstream gene promoters and begin transcription.

<span class="mw-page-title-main">TATA-binding protein</span> Protein-coding gene in the species Homo sapiens

The TATA-binding protein (TBP) is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 30 base pairs upstream of the transcription start site in some eukaryotic gene promoters.

<span class="mw-page-title-main">POLR2A</span> Protein-coding gene in the species Homo sapiens

DNA-directed RNA polymerase II subunit RPB1, also known as RPB1, is an enzyme that is encoded by the POLR2A gene in humans.

<span class="mw-page-title-main">MED1</span> Protein-coding gene in the species Homo sapiens

Mediator of RNA polymerase II transcription subunit 1 also known as DRIP205 or Trap220 is a subunit of the Mediator complex and is a protein that in humans is encoded by the MED1 gene. MED1 functions as a nuclear receptor coactivator.

<span class="mw-page-title-main">MED12</span> Protein-coding gene in humans

Mediator of RNA polymerase II transcription, subunit 12 homolog , also known as MED12, is a human gene found on the X chromosome.

<span class="mw-page-title-main">SUB1</span> Protein-coding gene in the species Homo sapiens

Activated RNA polymerase II transcriptional coactivator p15 also known as positive cofactor 4 (PC4) or SUB1 homolog is a protein that in humans is encoded by the SUB1 gene. The human SUB1 gene is named after an orthologous gene in yeast.

<span class="mw-page-title-main">CCNC (gene)</span> Protein-coding gene in the species Homo sapiens

Cyclin-C is a protein that in humans is encoded by the CCNC gene.

<span class="mw-page-title-main">Cyclin-dependent kinase 8</span> Protein-coding gene in the species Homo sapiens

Cell division protein kinase 8 is an enzyme that in humans is encoded by the CDK8 gene.

<span class="mw-page-title-main">MED24</span> Protein-coding gene in the species Homo sapiens

Mediator of RNA polymerase II transcription subunit 24 is an enzyme that in humans is encoded by the MED24 gene.

<span class="mw-page-title-main">MED21</span> Protein-coding gene in the species Homo sapiens

Mediator of RNA polymerase II transcription subunit 21 is an enzyme that in humans is encoded by the MED21 gene.

<span class="mw-page-title-main">MED6</span> Protein-coding gene in the species Homo sapiens

Mediator of RNA polymerase II transcription subunit 6 is one of the subunits of the Mediator complex. It is an enzyme that in humans is encoded by the MED6 gene.

<span class="mw-page-title-main">MED4</span> Protein-coding gene in the species Homo sapiens

Mediator of RNA polymerase II transcription subunit 4 also known as mediator complex subunit 4 (MED4), a component of Mediator or vitamin D3 receptor-interacting protein complex 36 kDa component (DRIP36) is a protein that in humans is encoded by the MED4 gene.

<span class="mw-page-title-main">MED15</span> Protein-coding gene in the species Homo sapiens

Mediator of RNA polymerase II transcription subunit 15, also known as Gal11, Spt13 in yeast and PCQAP, ARC105, or TIG-1 in humans is a protein encoded by the MED15 gene.

<span class="mw-page-title-main">MED17</span> Protein-coding gene in the species Homo sapiens

Mediator of RNA polymerase II transcription subunit 17 is an enzyme that in humans is encoded by the MED17 gene.

<span class="mw-page-title-main">MED25</span> Protein-coding gene in the species Homo sapiens

Mediator of RNA polymerase II transcription subunit 25 is an enzyme that in humans is encoded by the MED25 gene.

<span class="mw-page-title-main">MED27</span> Protein-coding gene in the species Homo sapiens

Mediator of RNA polymerase II transcription subunit 27 is an enzyme that in humans is encoded by the MED27 gene. It forms part of the Mediator complex.

<span class="mw-page-title-main">MED26</span> Protein-coding gene in the species Homo sapiens

Mediator of RNA polymerase II transcription subunit 26 is an enzyme that in humans is encoded by the MED26 gene. It forms part of the Mediator complex.

RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters of protein-coding genes in living cells. It consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins known as SRB proteins.

<span class="mw-page-title-main">MED13</span> Protein-coding gene in the species Homo sapiens

Mediator complex subunit 13 is a protein that in humans is encoded by the MED13 gene.

The transactivation domain or trans-activating domain (TAD) is a transcription factor scaffold domain which contains binding sites for other proteins such as transcription coregulators. These binding sites are frequently referred to as activation functions (AFs). TADs are named after their amino acid composition. These amino acids are either essential for the activity or simply the most abundant in the TAD. Transactivation by the Gal4 transcription factor is mediated by acidic amino acids, whereas hydrophobic residues in Gcn4 play a similar role. Hence, the TADs in Gal4 and Gcn4 are referred to as acidic or hydrophobic, respectively.

References

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  2. ↑ Flanagan PM, Kelleher RJ, Sayre MH, Tschochner H, Kornberg RD (April 1991). "A mediator required for activation of RNA polymerase II transcription in vitro". Nature. 350 (6317): 436–8. Bibcode:1991Natur.350..436F. doi:10.1038/350436a0. PMID   2011193. S2CID   4323957.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Allen BL, Taatjes DJ (March 2015). "The Mediator complex: a central integrator of transcription". Nature Reviews Molecular Cell Biology. 16 (3): 155–66. doi:10.1038/nrm3951. PMC   4963239 . PMID   25693131.
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  17. ↑ Kato Y, Habas R, Katsuyama Y, Näär AM, He X (2002). "A component of the ARC/Mediator complex required for TGF beta/Nodal signalling". Nature. 418 (6898): 641–6. Bibcode:2002Natur.418..641K. doi:10.1038/nature00969. PMID   12167862. S2CID   4330754.
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  20. ↑ Chen, Rong; Jiang, Hongling; Li, Lin; Zhai, Qingzhe; Qi, Linlin; Zhou, Wenkun; Liu, Xiaoqiang; Li, Hongmei; Zheng, Wenguang; Sun, Jiaqiang; Li, Chuanyou (July 2012). "The Arabidopsis Mediator Subunit MED25 Differentially Regulates Jasmonate and Abscisic Acid Signaling through Interacting with the MYC2 and ABI5 Transcription Factors". The Plant Cell. 24 (7): 2898–2916. doi: 10.1105/tpc.112.098277 . PMC   3426122 . PMID   22822206.
  21. ↑ Sun, Wenjing; Han, Hongyu; Deng, Lei; Sun, Chuanlong; Xu, Yiran; Lin, Lihao; Ren, Panrong; Zhao, Jiuhai; Zhai, Qingzhe; Li, Chuanyou (November 2020). "Mediator Subunit MED25 Physically Interacts with PHYTOCHROME INTERACTING FACTOR4 to Regulate Shade-Induced Hypocotyl Elongation in Tomato". Plant Physiology. 184 (3): 1549–1562. doi: 10.1104/pp.20.00587 . PMC   7608172 . PMID   32938743.
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  37. 1 2 Landles C, Chalk S, Steel JH, Rosewell I, Spencer-Dene B, Lalani el-N, Parker MG (2003). "The thyroid hormone receptor-associated protein TRAP220 is required at distinct embryonic stages in placental, cardiac, and hepatic development". Mol Endocrinol. 17 (12): 2418–35. doi: 10.1210/me.2003-0097 . PMID   14500757.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  38. ↑ Huszar JM, Jia Y, Reddy JK, Payne CJ (2015). "Med1 regulates meiotic progression during spermatogenesis in mice". Reproduction. 149 (6): 597–604. doi:10.1530/REP-14-0483. PMC   4417004 . PMID   25778538.
  39. ↑ Noguchi F, Nakajima T, Inui S, Reddy JK, Itami S (2014). "Alteration of skin wound healing in keratinocyte-specific mediator complex subunit 1 null mice". PLOS ONE. 9 (8): e102271. Bibcode:2014PLoSO...9j2271N. doi: 10.1371/journal.pone.0102271 . PMC   4133190 . PMID   25122137.
  40. ↑ Yoshizaki K, Hu L, Nguyen T, Sakai K, He B, Fong C, Yamada Y, Bikle DD, Oda Y (2014). "Ablation of coactivator Med1 switches the cell fate of dental epithelia to that generating hair". PLOS ONE. 9 (6): e99991. Bibcode:2014PLoSO...999991Y. doi: 10.1371/journal.pone.0099991 . PMC   4065011 . PMID   24949995.
  41. 1 2 3 Bourbon HM, Aguilera A, Ansari AZ, Asturias FJ, Berk AJ, Bjorklund S, et al. (2004). "A unified nomenclature for protein subunits of mediator complexes linking transcriptional regulators to RNA polymerase II". Molecular Cell. 14 (5): 553–7. doi: 10.1016/j.molcel.2004.05.011 . PMID   15175151.
  42. ↑ Gene names derived from "UniProtKB" . Retrieved 12 October 2012.
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