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Zooming in on Transcription Preinitiation Gupta, K. , Sari-Ak, D., Haffke, M., Trowitzsch, S., & Berger, I. (2016). Zooming in on Transcription Preinitiation. Journal of Molecular Biology, 428(12), 2581-2591. https://doi.org/10.1016/j.jmb.2016.04.003 Publisher's PDF, also known as Version of record License (if available): CC BY-NC-ND Link to published version (if available): 10.1016/j.jmb.2016.04.003 Link to publication record in Explore Bristol Research PDF-document This is the corrected proof version of the article (version of record). It first appeared online via Elsevier at http://www.sciencedirect.com/science/article/pii/S0022283616300468. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ Article KDC YJMBI-65053; No. of pages: 11; 4C: 2, 3, 4, 5, 6, 7 Zooming in on Transcription Preinitiation Kapil Gupta 1,2, Duygu Sari-Ak 1,2, Matthias Haffke 3, Simon Trowitzsch 4 and Imre Berger 1,2,5 1 - European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, 38042, Grenoble Cedex 9, France 2 - Unit of Virus Host-Cell Interactions, University of Grenoble Alpes-EMBL-CNRS, UMI 3265, 71 Avenue des Martyrs, 38042, Grenoble, Cedex 9, France 3 - Center for Proteomic Chemistry, Structural Biophysics, Novartis Institute for Biomedical Research NIBR, Fabrikstrasse 2, 4056 Basel, Switzerland 4 - Institute of Biochemistry, Biocenter, Goethe-Universität Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt/Main Germany 5 - The School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK Correspondence to Imre Berger: The School of Biochemistry, University of Bristol, University Walk, Clifton, BS8 1TD, Bristol, UK. [email protected] http://dx.doi.org/10.1016/j.jmb.2016.04.003 Edited by Lori A Passmore Abstract Class II gene transcription commences with the assembly of the Preinitiation Complex (PIC) from a plethora of proteins and protein assemblies in the nucleus, including the General Transcription Factors (GTFs), RNA polymerase II (RNA pol II), co-activators, co-repressors, and more. TFIID, a megadalton-sized multiprotein complex comprising 20 subunits, is among the first GTFs to bind the core promoter. TFIID assists in nucleating PIC formation, completed by binding of further factors in a highly regulated stepwise fashion. Recent results indicate that TFIID itself is built from distinct preformed submodules, which reside in the nucleus but also in the cytosol of cells. Here, we highlight recent insights in transcription factor assembly and the regulation of transcription preinitiation. © 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Introduction was identified as a global regulator of gene expression [2–4]. Functional and structural analyses of many Class II gene transcription is a tightly regulated, components of this striking complexity have provided essential process controlled by a highly complex immense insights into the transcription process. In this multicomponent machinery. A plethora of proteins, contribution, we are reviewing, by no means exhaus- more than a hundred in humans, are organized in tively, recent important findings about key architec- often very large multiprotein assemblies including tures within the transcription machinery, leading to General Transcription Factors (GTFs TFIIA, TFIIB, conceptual advances in terms of complex assembly TFIID, TFIIE, TFIIF, TFIIH), RNA polymerase (RNA and function, with a focus on the key GTF that pol II), and a large number of diverse complexes nucleates PIC formation, TFIID. that act as co-activators, co-repressors, chromatin modifiers and remodelers (Fig. 1). Class II gene transcription is regulated at various levels: while PIC Assembly: Lessons from Yeast and assembling on chromatin, before and during transcrip- Human tion initiation, throughout elongation and mRNA processing, and termination. A host of activators and Transcription of RNA pol II-dependent genes is repressors has been reported to regulate transcription triggered by the regulated assembly of the Preinitia- [1]. A central multisubunit complex called the Mediator tion Complex (PIC). PIC formation commences with 0022-2836/© 2016 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). J Mol Biol (2016) xx, xxx–xxx Please cite this article as: K. Gupta, et al., Zooming in on Transcription Preinitiation, J. Mol. Biol. (2016), http://dx.doi.org/10.1016/ j.jmb.2016.04.003 2 Transcription Preinitiation transcription rate in subsequent rounds of transcription [12,15].Promoterescapeisprecededbyanabortive transcription in many systems, where multiple short RNA products of 3 to 10 bases in length are synthesized [16,17]. Recent landmark studies on human and yeast PIC formation provided more differentiated views of the first steps in the transcription initiation process, corroborating the concept of stepwise assembly while also hinting at significant differences that may be present between the species [18,19] (reviewed in Ref. [20]). In the study of the human PIC, the proposed assembly mechanism follows the “con- ventional” stepwise order with the exception that Fig. 1. Transcription PIC. Class II gene transcription is RNA pol II appears to be already recruited at the very brought about by (in humans) over a hundred polypeptides beginning, before TFIIF is accreted [18]. According assembling on the core promoter of protein-encoding genes, to this model, TFIIF functions in reorganizing the which then give rise to messenger RNA. A PIC on a core growing PIC, rather than loading RNA pol II into it. promoter is shown in a schematic representation (adapted TFIIH is the last component to be recruited [18]. from Ref. [5]). PIC contains, in addition to promoter DNA, the According to the model put forward based on the GTFsTFIIA,B,D,E,F,andH,andRNAPolII.PICassembly studies from yeast, all GTFs (except TFIIF) including is thought to occur in a highly regulated, stepwise fashion TFIIH assemble into a PIC lacking RNA pol II, which, (top). TFIID is among the first GTFs to bind the core promoter via its TBP subunit. Nucleosomes at transcription start sites together with TFIIF, is the last to be incorporated contribute to PIC assembly, mediated by signaling through [19]. The structures and models presented in these epigenetic marks on histone tails. The Mediator (not shown) ground-breaking reports provide a wealth of archi- is a further central multiprotein complex identified as a global tectural and functional insight into PIC assembly and transcriptional regulator. TATA, TATA-box DNA; BREu,B convey that there may be different ways to organize recognition element upstream; BREd, B recognition element PIC in space and time, and that differences between downstream; Inr, Initiator; DPE, Down-stream promoter the species may exist [18,19]. In a separate study, element. the architecture of a yeast initially transcribing complex (ITC) was determined [21].ITCisan the binding of TFIID to the core promoter. TFIID intermediate complex formed during PIC assembly contains the TATA-box binding protein (TBP). by RNA pol II, TFIIF, TFIIB, TBP, and DNA, as well Binding of TFIID to the core-promoter is followed as a small nascent RNA [21]. Interestingly, this study by the recruitment of further GTFs and RNA pol II. revealed similarities with the model of human ITC Several lines of evidence suggest that this process [18], suggesting that the core architecture of PIC is occurs in a defined, stepwise order and undergoes conserved between yeast and human. significant restructuring [5]. First, PIC adopts an Notably, the described studies above used TBP inactive state, the “closed” complex, which is incompe- instead of holo–TFIID. TBP has been shown to suffice tent to initiate transcription. The ATP-dependent for basal transcription, whereas holo–TFIID is required translocase activity of the XPB/Ssl2 helicase subunit for activated transcription [22,23]. Therefore, it is of GTF TFIIH then opens up about 11 to 15 base pairs conceivable that PIC assembly may follow alternative around the transcription start site by moving along one pathways in activated transcription. DNA strand inducing torsional strain, leading to conformational rearrangements and positioning of single-stranded DNA to the active site of RNA pol II Mediator Core–RNA Pol II Initially [6–9].Inthis“open” complex, RNA pol II can enter Transcribing Complex elongation to transcribe throughout a gene in a highly processive manner without dissociating from the DNA Recently, single particle cryo-electron microscopy template or losing the nascent RNA. In most eukary- (cryo-EM) and crosslinking mass spectrometry otes, after synthesizing about 20–100 bases, RNA pol (CLMS) studies of a yeast ITC bound to a Mediator II can pause (Promoter proximal pause) and then core complex revealed important first insights into disconnect from promoter elements and other compo- transcription initiation and PIC assembly, suggesting nents of the transcription machinery, giving rise to a fully that Mediator is involved in stabilizing PIC and functional elongation complex in a process called in activating RNA pol II [24]. The architecture of promoter escape [10–14]. The promoter-bound com- Mediator-ITC is shown in Fig. 2. The cryo-EM ponents of the PIC, in contrast, remain in place, and structure was determined at nanometer resolution, thus only TFIIB, TFIIF, and RNA pol II need to be and CLMS proved to be instrumental to decipher the recruited for re-initiation, significantly increasing the subunit topology of the Mediator Middle module. Please cite this article as: K. Gupta, et al., Zooming in on Transcription Preinitiation, J. Mol. Biol. (2016), http://dx.doi.org/10.1016/ j.jmb.2016.04.003 Transcription Preinitiation 3 Fig.
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