The Mediator complex as a master regulator of transcription by RNA polymerase II

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(11), P. 732 - 749

Published: June 20, 2022

Language: Английский

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Functional partitioning of transcriptional regulators by patterned charge blocks

Cell, Journal Year: 2023, Volume and Issue: 186(2), P. 327 - 345.e28

Published: Jan. 1, 2023

Language: Английский

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Structures of the human Mediator and Mediator-bound preinitiation complex

Science, Journal Year: 2021, Volume and Issue: 372(6546)

Published: May 7, 2021

A complete PIC-Mediator structure As a critical transcription coactivator, the multisubunit Mediator complex binds RNA polymerase II (Pol II), facilitates preinitiation (PIC) assembly, and stimulates phosphorylation of Pol C-terminal domain (CTD). However, how these transcriptional events are coordinated by is not fully understood. Chen et al. determined structures human Mediator-bound PIC in distinct conformational states, latter which represents assembled on 14-subunit factor IID (TFIID). The show that undergoes reorganization during sandwiches CTD, works with TFIID to organize TFIIH for initiation. Science , abg0635, this issue p. eabg0635

Language: Английский

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Structure of the human Mediator–RNA polymerase II pre-initiation complex

Nature, Journal Year: 2021, Volume and Issue: 594(7861), P. 129 - 133

Published: April 26, 2021

Language: Английский

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Enhanced T cell effector activity by targeting the Mediator kinase module

Science, Journal Year: 2022, Volume and Issue: 378(6620)

Published: Nov. 10, 2022

T cells are the major arm of immune system responsible for controlling and regressing cancers. To identify genes limiting cell function, we conducted genome-wide CRISPR knockout screens in human chimeric antigen receptor (CAR) cells. Top hits were

Language: Английский

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Structural insights into nuclear transcription by eukaryotic DNA-dependent RNA polymerases

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(9), P. 603 - 622

Published: May 3, 2022

Language: Английский

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3D enhancer-promoter interactions and multi-connected hubs: Organizational principles and functional roles

Cell Reports, Journal Year: 2023, Volume and Issue: 42(4), P. 112068 - 112068

Published: April 1, 2023

The spatiotemporal control of gene expression is dependent on the activity cis-acting regulatory sequences, called enhancers, which regulate target genes over variable genomic distances and, often, by skipping intermediate promoters, suggesting mechanisms that enhancer-promoter communication. Recent genomics and imaging technologies have revealed highly complex interaction networks, whereas advanced functional studies started interrogating forces behind physical communication among multiple enhancers promoters. In this review, we first summarize our current understanding factors involved in communication, with a particular focus recent papers new layers complexities to old questions. second part subset connected "hubs" discuss their potential functions signal integration regulation, as well putative might determine dynamics assembly.

Language: Английский

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The Mediator kinase module: an interface between cell signaling and transcription

Trends in Biochemical Sciences, Journal Year: 2022, Volume and Issue: 47(4), P. 314 - 327

Published: Feb. 19, 2022

The Mediator kinase module transforms function through physical interaction and its activity.The regulates transcription by altering factor at enhancers promoters.Rapid, stimulus-specific transcriptional responses are enabled the module.By controlling (TF) polymerase II (pol II) activity, helps convert signaling inputs to outputs. complex controls RNA activity coordinating assembly of pol regulatory factors start sites mediating interactions between enhancer-bound (TFs) enzyme. structure is completely altered upon binding module, a multi-subunit that contains CDK8 or vertebrate-specific paralog CDK19. Here, we review mechanisms which transcription, emphasizing impact on TF elongation, enhancer function, chromatin architecture. We also highlight how integrates pathways with enable rapid, responses, as well links human disease. (see Glossary) genome-wide regulator transcription; consequently, itself targeted an array regulate function. For example, sequence-specific, DNA-binding TFs bind control recruitment specific genomic loci. Also, reversibly associates (forming what here call CDK-Mediator) in several ways. Conserved from yeast humans, consists four subunits: kinase, CCNC, MED12, MED13. However, vertebrates evolved subunit paralogs, called CDK19, MED12L, MED13L (Box 1), expand functional diversity ways remain poorly defined. Not surprisingly, subunits required for mammalian embryogenesis [1.Li N. et al.Cyclin C haploinsufficient tumour suppressor.Nat. Cell Biol. 2014; 16: 1080-1091Google Scholar, 2.Miao Y.L. al.Mediator component MED13 zygotic genome activation postimplantation development mouse.Biol. Reprod. 2018; 98: 449-464Google 3.Westerling T. al.Cdk8 essential preimplantation mouse development.Mol. Cell. 2007; 27: 6177-6182Google 4.Rocha P.P. al.Med12 early canonical Wnt Wnt/PCP signaling.Development. 2010; 137: 2723-2731Google Scholar] linked myriad diseases 2).Box 1Vertebrate-specific paralogs subunitsThe conserved among eukaryotes, but CDK8, emerged (Figure I). Each expressed different chromosomes appears be mutually exclusive within [52.Galbraith M.D. al.HIF1A employs CDK8-Mediator stimulate RNAPII elongation response hypoxia.Cell. 2013; 153: 1327-13239Google Scholar]. Comparatively little known about these connections disease have been discovered (Table S1 supplemental information online).CDK8 CDK19 highest sequence identity inhibitors invariably block both proteins. show evidence redundant [109.Sooraj D. al.MED12 BRD4 cooperate sustain cancer growth loss mediator kinase.Mol. 2022; 82: 123-139Google nonredundant functions each has shown kinase-dependent -independent [25.Steinparzer I. al.Transcriptional IFN-gamma require pause release mechanistically distinct functions.Mol. 2019; 76: 485-499Google Scholar,87.Audetat K.A. al.A kinase-independent role cyclin-dependent 19 p53 response.Mol. 2017; 37e00626-16Google Scholar,109.Sooraj Scholar,117.Menzl BCR-ABL1(+) leukemia.Nat. Commun. 10: 4741Google Scholar].The MED12 protein implicated numerous X-linked online) X chromosome, whereas MED12L gene resides chromosome 3. Interestingly, Xist repression (CDK19 no effect) mice [118.Postlmayr A. establishment H3K27me3 development.Development. 2020; 147dev175141Google shows more restricted expression across tissues compared MED12. Whereas necessary [8.Park M.J. al.Oncogenic exon 2 mutations disrupt allosteric cyclin C-CDK8/19.J. Chem. 293: 4870-4882Google Scholar,81.Knuesel M.T. al.The subcomplex histone requires Med12 can independently Mediator.Mol. 2009; 29: 650-661Google Scholar], it unknown whether activates CDK8/19 similarity N-terminal helix I) suggests similar activation.One basic link [10.Knuesel molecular switch co-activator function.Genes Dev. 23: 439-451Google Scholar,11.Tsai K.L. Mediator-CDK8 association Mediator-RNA interaction.Nat. Struct. Mol. 20: 611-619Google Notably, proteomics data suggest modules containing (instead MED13) maintain [39.Ebmeier C.C. Taatjes D.J. Activator-Mediator Mediator-cofactor interactions.Proc. Natl. Acad. Sci. U. S. 107: 11283-11288Google Scholar,119.Sato set consensus identified multidimensional identification technology.Mol. 2004; 14: 685-691Google Moreover, ubiquitylated FBW7, initiates dissociation degradation [110.Davis M.A. SCF-Fbw7 ubiquitin ligase degrades Mediator.Genes 151-156Google Clinical similar, not identical, biological roles online).Box 2Mediator diseaseMutations cause disability online), broadly grouped into two categories: neurological/developmental disorders (reviewed [7.Srivastava Kulshreshtha R. Insights clinical relevance subunit, diseases.J. Physiol. 2021; 236: 3163-3177Google Scholar]). In addition, wide range cancers subunits, summarized recent reviews [121.Dannappel M.V. al.Molecular vivo modules.Front. 6: 171Google Scholar,122.Roninson I.B. al.Identifying impacted CDK8/19.Cells. 8: 821Google Scholar].Three medically related intellectual/developmental syndromes MED12: Opitz-Kaveggia, Lujan, Ohdo syndrome. Furthermore, domains associated intellectual exhibit comparable phenotypes individuals online). introduction could compensate deletion Drosophila, mutant neurological not, resulting seizures reduced fitness surviving flies [123.Chung H.L. al.De novo variants syndrome involving epileptic encephalopathy.Am. J. Hum. Genet. 106: 717-725Google Likewise, induced pathogenic mutants resulted developmental defects [124.Tian al.Somatic de germline MEDs neural tube defects.Front. 9641831Google These results disease-associated CDK19.Mutations nonmalignant uterine leiomyoma most well-studied changes enhancer-promoter looping architecture [79.Moyo M.B. al.Altered landscape engagement underlie dysregulation leiomyomas.Nat. 11: 1019Google negatively Scholar,9.Turunen M. al.Uterine leiomyoma-linked mediator-associated CDK activity.Cell Rep. 7: 654-660Google Such consistent regulation super-enhancer [67.Kuuluvainen E. al.Depletion represses superenhancer-associated genes colon cells.Mol. 38e00573-17Google Scholar,74.Pelish H.E. inhibition further super-enhancer-associated AML.Nature. 2015; 526: 273-276Google Scholar,75.Lynch C.J. al.Global hyperactivation stabilizes naive pluripotency kinases.Nat. 22: 1223-1238Google Scholar].Targeting therapeutic benefit remains work progress, novel strategies continue emerge. Firestein lab showed bromodomain extraterminal domain (BET) (e.g., JQ1) may complement + certain compensatory increases occupancy BET were observed double knockout cells (HCT116 DLD1), suggesting cooperativity agreement other studies [51.Donner A.J. al.CDK8 positive serum network.Nat. 17: 194-201Google Scholar,125.Bhagwat A.S. al.BET releases select cis-regulatory elements.Cell 2016; 15: 519-530Google activation. One Mutations Three Targeting Although current structural only CDK8-CCNC dimer [5.Schneider E.V. CDK8/CycC implicates specificity CDK/cyclin family reveals deep pocket binder.J. 2011; 412: 251-266Google cryogenic electron microscopy (cryoEM) (Saccharomyces cerevisiae) was recently determined Tsai [6.Li Y.C. al.Structure noncanonical Cdk8 mechanism Argonaute-containing module.Sci. Adv. 7eabd4484Google This provided first high-resolution large Med13 subunits. key module. N terminus interacts Cdk8–Ccnc 1). mutated variety clustering around residues 36–44 Structural coworkers occupy complex. otherwise disordered loop, allows substrate access active site Additionally, prior Boyer oncogenic model Med12-dependent likely humans. While details available, Cramer completed crosslinking-mass spectrometry analysis (S. CDK-Mediator [12.Osman II.J. 296100734Google extensive Mediator, including and/or Med19 Med10, Med10 reside hook [13.Zhao H. Tail core.Nat. 12: 1355Google represents interface TFIIH-associated later). this review, some considering past context results. enables cell cascades help 'reprogram' patterns changing conditions. then discuss module-dependent stages (initiation, pausing, elongation) new clarified expanded biochemical cell-based experiments. Finally, represent powerful elements coordinate type- programs outline contribute looping. Throughout, areas understanding limited conclude open questions future research. genome-wide, remodelers, way, serve 'master regulators' pre-initiation (PIC) Activation causes phosphorylation nuclear localization 2). As examples: (i) interferon-induced STAT triggers their allow target activation, (ii) ELK1 phosphorylated during MAPK pathway enhances ELK1-dependent [14.Balamotis al.Complexity domain-Mediator interface.Sci. Signal. 2: ra20Google representative examples, endpoints cascades. Importantly, common targets kinases later), yielding direct signaling. Coordination evident ancient metabolism. Signaling metabolic integrated interdependent, such will trigger adaptation, vice versa 2) [15.Zhu Thompson C.B. Metabolic proliferation.Nat. Rev. 436-450Google flux directly enzymes phosphorylation), they modulate well. organisms cerevisiae, coordinates nutrients [16.Khakhina al.Med13p prevents mitochondrial fission programmed death retention C.Mol. 25: 2807-2816Google 17.Lindsay A.K. al.Analysis Candida albicans defective reveal metabolism biofilm formation.PLoS 10e1004567Google 18.Mousley sterol-binding endosomal lipid TOR nitrogen sensing.Cell. 2012; 148: 702-715Google via [19.Hirst al.GAL4 regulated holoenzyme-associated SRB10/CDK8.Mol. 1999; 3: 673-678Google Scholar,20.Nelson C. al.Srb10/Cdk8 filamentous phosphorylating Ste12.Nature. 2003; 421: 187-190Google Similarly, indirectly metazoans modification TFs. cells, phosphorylates major regulators metabolism, SREBP [21.Zhao X. al.Regulation lipogenesis 8-mediated SREBP-1.J. Clin. Invest. 122: 2417-2427Google Notch ICD Scholar,22.Fryer al.Mastermind recruits CycC:Cdk8 phosphorylate notch turnover.Mol. 509-520Google SMAD1/3 [23.Alarcon al.Nuclear CDKs drive Smad turnover BMP TGF-b pathways.Cell. 139: 757-769Google STAT1/3/5a [24.Bancerek STAT1 selectively interferon response.Immunity. 38: 250-262Google insulin, WNT/β-catenin, TGFβ, cascades, respectively. CDK8-dependent stability co

Language: Английский

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Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(7), P. 574 - 591

Published: Feb. 27, 2024

Language: Английский

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Bridging structural and cell biology with cryo-electron microscopy

Nature, Journal Year: 2024, Volume and Issue: 628(8006), P. 47 - 56

Published: April 3, 2024

Language: Английский

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