p53 activates transcription by directing structural shifts in Mediator

Meyer, Krista; Lin, Shih-Chieh; Bernecky, Carrie; Gao, Yuefeng; Taatjes, Dylan J.

doi:10.1038/nsmb.1816

Cited by 124 publications

(162 citation statements)

References 56 publications

(86 reference statements)

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“…The mechanisms through which Mediator might act to facilitate pol IIG function are not known, but it is relevant that TFIIF serves to specifically align pol II with Mediator (35,36). This effect of TFIIF depends on the interaction of an activator with Mediator (35), consistent with the earlier observation that activators can drive structural changes in Mediator (37). Thus, Mediator may facilitate the otherwise weak ability of TFIIF to support PIC assembly despite the presence of Gdown1.…”

Section: Discussionsupporting

confidence: 73%

Functional Interactions of the RNA Polymerase II-interacting Proteins Gdown1 and TFIIF

Davis

Guo²,

Price

et al. 2014

Journal of Biological Chemistry

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“…In addition, all the 40 predicted Med26 subunits showed the Pfam Med26 domain having the conserved TFIIS helical bundle domain, a conserved N-terminal region found in the transcription elongation factors TFIIS and Elongin A (Booth et al, 2000). Although the role of Med26 in plants remains to be established, it appears that Med26 may play a role in transcription elongation, as has been reported for the Cdk8 submodule in the serum response network (Donner et al, 2010) and in p53-directed Pol II elongation via the Med complex in humans (Meyer et al, 2010). For each core module of the Med (head, middle, and tail), a high conservation except for one or two subunits was observed across kingdoms.…”

Section: Evidence Of Animal Med26 In Plantsmentioning

confidence: 88%

“…The Med complex has the flexibility to acquire different structures upon binding of different activators to different/same subunits (Taatjes et al, 2002(Taatjes et al, , 2004. These distinct activator-Med structures differentially affect Pol II activity (Meyer et al, 2010) and regulate Med function in genespecific ways . Although the function of Med as a GTF has been widely accepted (Takagi and Kornberg, 2006), its role as a global regulator of transcription has been questioned in some recent reports (Deato et al, 2008;Thiaville et al, 2008).…”

mentioning

confidence: 99%

The Mediator Complex in Plants: Structure, Phylogeny, and Expression Profiling of Representative Genes in a Dicot (Arabidopsis) and a Monocot (Rice) during Reproduction and Abiotic Stress

et al. 2011

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The Mediator (Med) complex relays regulatory information from DNA-bound transcription factors to the RNA polymerase II in eukaryotes. This macromolecular unit is composed of three core subcomplexes in addition to a separable kinase module. In this study, conservation of Meds has been investigated in 16 plant species representing seven diverse groups across the plant kingdom. Using Hidden Markov Model-based conserved motif searches, we have identified all the known yeast/metazoan Med components in one or more plant groups, including the Med26 subunits, which have not been reported so far for any plant species. We also detected orthologs for the Arabidopsis (Arabidopsis thaliana) Med32, -33, -34, -35, -36, and -37 in all the plant groups, and in silico analysis identified the Med32 and Med33 subunits as apparent orthologs of yeast/metazoan Med2/ 29 and Med5/24, respectively. Consequently, the plant Med complex appears to be composed of one or more members of 34 subunits, as opposed to 25 and 30 members in yeast and metazoans, respectively. Despite low similarity in primary Med sequences between the plants and their fungal/metazoan partners, secondary structure modeling of these proteins revealed a remarkable similarity between them, supporting the conservation of Med organization across kingdoms. Phylogenetic analysis between plant, human, and yeast revealed single clade relatedness for 29 Med genes families in plants, plant Meds being closer to human than to yeast counterparts. Expression profiling of rice (Oryza sativa) and Arabidopsis Med genes reveals that Meds not only act as a basal regulator of gene expression but may also have specific roles in plant development and under abiotic stress conditions.

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“…The functional bivalency of CDK8 is quite enigmatic, but structural studies may provide a clue. Mediators exhibit a structural change when they bind various types of transcriptional activators (60) and therefore exist as multiple structurally distinct subcomplexes. Some of these subcomplexes may bind tightly to PRMT5 and act as corepressors, as described in this paper, whereas others may lack PRMT5 and act as coactivators.…”

Section: Dissociation Of Mediator Cdks From C/ebp␤ Target Genes Changmentioning

confidence: 99%

Mediator Complex Recruits Epigenetic Regulators via Its Two Cyclin-dependent Kinase Subunits to Repress Transcription of Immune Response Genes

Tsutsui¹,

Fukasawa

Shinmyouzu

et al. 2013

Journal of Biological Chemistry

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Background: Two CDK subunits of the Mediator complex play pivotal roles in transcription by a mechanism that has not yet been elucidated. Results: The histone arginine methyltransferase PRMT5 is a Mediator CDK-interacting protein. Conclusion:Mediator-associated PRMT5 symmetrically dimethylates histone H4 arginine 3, and this might cause transcriptional repression. Significance: This work enables further exploration of Mediator functions in transcriptional repression.

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“…In organisms as diverse as budding yeast and mammals, Mediator adopts a similar overall architecture characterized by the presence of four modules termed head, middle, tail, and kinase (Cai et al 2009 (Malik et al 2007). Third, p53-induced changes in the conformational state of Mediator were found to stimulate stalled, promoter-proximal Pol II molecules to productive elongation both in vitro and in cells (Meyer et al 2010). Fourth, Cdk8 was observed to be a potent regulator of Pol II elongation at serum-responsive genes in human cells, as its knockdown impaired Pol II elongation and correlated with decreased levels of CTD phosphorylation at Ser2 and Ser5.…”

mentioning

confidence: 99%

Role of Mediator in Regulating Pol II Elongation and Nucleosome Displacement in Saccharomyces cerevisiae

Kremer

Kim²,

Jeon³

et al. 2012

Genetics

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Mediator is a modular multisubunit complex that functions as a critical coregulator of RNA polymerase II (Pol II) transcription. While it is well accepted that Mediator plays important roles in the assembly and function of the preinitiation complex (PIC), less is known of its potential roles in regulating downstream steps of the transcription cycle. Here we use a combination of genetic and molecular approaches to investigate Mediator regulation of Pol II elongation in the model eukaryote, Saccharomyces cerevisiae. We find that ewe (expression without heat shock element) mutations in conserved Mediator subunits Med7, Med14, Med19, and Med21-all located within or adjacent to the middle module-severely diminish heat-shock-induced expression of the Hsf1-regulated HSP82 gene. Interestingly, these mutations do not impede Pol II recruitment to the gene's promoter but instead impair its transit through the coding region. This implies that a normal function of Mediator is to regulate a postinitiation step at HSP82. In addition, displacement of histones from promoter and coding regions, a hallmark of activated heat-shock genes, is significantly impaired in the med14 and med21 mutants. Suggestive of a more general role, ewe mutations confer hypersensitivity to the antielongation drug 6-azauracil (6-AU) and one of them-med21-impairs Pol II processivity on a GAL1-regulated reporter gene. Taken together, our results suggest that yeast Mediator, acting principally through its middle module, can regulate Pol II elongation at both heat-shock and non-heat-shock genes. IN eukaryotes, transcription of the DNA template into premRNA by RNA polymerase II (Pol II) occurs in a welldefined, stepwise fashion. First, chromatin, the nucleoprotein complex in which the DNA is packaged, must unfold into a 10 nm, beads-on-a-string filament, and for many genes a nucleosome-free region needs to be created over the core promoter (Venters and Pugh 2009). Both are achieved via activator-mediated recruitment of chromatin modification and remodeling enzymes (reviewed in Li et al. 2007). Once a permissive chromatin template has been created, Pol II and the other general transcription factors then bind the core promoter, where they are assembled into a preinitiation complex (PIC; formally analogous to the closed RNA polymerase complex in prokaryotes). Next, Pol II forms an open complex concomitant with ATP-dependent melting of the DNA strands and initiates transcription following phosphorylation of its C-terminal repeat domain (CTD) at Ser5 residues by the TFIIH kinase, Cdk7. Following synthesis of 25-30 nucleotides, Pol II pauses, allowing the nascent RNA to be capped. Finally, Pol II transitions to productive elongation, which requires Ser2 phosphorylation of the CTD. In metazoans, this is catalyzed by P-TEFb and in yeast by Bur1 and Ctk1 (reviewed in Saunders et al. 2006).A key regulator of many of the above steps is Mediator, an evolutionarily conserved, modular multiprotein complex. Mediator acts as a signal transducer through its interac...

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p53 activates transcription by directing structural shifts in Mediator

Cited by 124 publications

References 56 publications

Functional Interactions of the RNA Polymerase II-interacting Proteins Gdown1 and TFIIF

The Mediator Complex in Plants: Structure, Phylogeny, and Expression Profiling of Representative Genes in a Dicot (Arabidopsis) and a Monocot (Rice) during Reproduction and Abiotic Stress

Mediator Complex Recruits Epigenetic Regulators via Its Two Cyclin-dependent Kinase Subunits to Repress Transcription of Immune Response Genes

Role of Mediator in Regulating Pol II Elongation and Nucleosome Displacement in Saccharomyces cerevisiae

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