Structure and mechanism of the RNA polymerase II transcription machinery.
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TLDR
A wealth of structural and functional data that have enabled a deeper understanding of Pol II transcription mechanisms are summarized and mechanistic questions that remain unanswered or controversial are highlighted.Abstract:
RNA polymerase II (Pol II) transcribes all protein-coding genes and many noncoding RNAs in eukaryotic genomes. Although Pol II is a complex, 12-subunit enzyme, it lacks the ability to initiate transcription and cannot consistently transcribe through long DNA sequences. To execute these essential functions, an array of proteins and protein complexes interact with Pol II to regulate its activity. In this review, we detail the structure and mechanism of over a dozen factors that govern Pol II initiation (e.g., TFIID, TFIIH, and Mediator), pausing, and elongation (e.g., DSIF, NELF, PAF, and P-TEFb). The structural basis for Pol II transcription regulation has advanced rapidly in the past decade, largely due to technological innovations in cryoelectron microscopy. Here, we summarize a wealth of structural and functional data that have enabled a deeper understanding of Pol II transcription mechanisms; we also highlight mechanistic questions that remain unanswered or controversial.read more
Citations
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A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers.
Laila El Khattabi,Haiyan Zhao,Jens Kalchschmidt,Natalie Young,Seolkyoung Jung,Peter Van Blerkom,Philippe Kieffer-Kwon,Kyong-Rim Kieffer-Kwon,Solji Park,Xiang Wang,Jordan Krebs,Subhash K. Tripathi,Noboru J. Sakabe,Débora R. Sobreira,Su-Chen Huang,Suhas S.P. Rao,Suhas S.P. Rao,Nathanael Pruett,Daniel Chauss,Erica Sadler,Andrea Lopez,Marcelo A. Nobrega,Erez Lieberman Aiden,Erez Lieberman Aiden,Erez Lieberman Aiden,Francisco J. Asturias,Rafael Casellas +26 more
TL;DR: It is proposed that Mediator's structural pliability enables it to integrate and transmit regulatory signals and act as a functional, rather than an architectural bridge, between promoters and enhancers.
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Mechanisms of enhancer action: the known and the unknown
TL;DR: A key regulator of differential gene expression programs are the enhancers, the gene-distal cis-regulatory sequences that govern spatiotemporal and quantitative expression dynamics of target genes.
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Two roles for the yeast transcription coactivator SAGA and a set of genes redundantly regulated by TFIID and SAGA.
TL;DR: Genome-wide mapping of SAGA and TFIID found binding of both factors at many genes independent of gene class, and promoter analysis suggests that the distinction between the gene classes is due to multiple components rather than any single regulatory factor or promoter sequence motif.
Journal ArticleDOI
Structure of the human Mediator–RNA polymerase II pre-initiation complex
TL;DR: In this paper, a recombinant version of human Mediator, reconstitute a 50-subunit Mediator-PIC complex and determine the structure of the complex by cryo-electron microscopy.
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Transcriptional Responses to IFN-γ Require Mediator Kinase-Dependent Pause Release and Mechanistically Distinct CDK8 and CDK19 Functions
Iris Steinparzer,Vitaly Sedlyarov,Jonathan D. Rubin,Kevin Eislmayr,Matthew D. Galbraith,Cecilia B. Levandowski,Terezia Vcelkova,Lucy Sneezum,Florian Wascher,Fabian Amman,Renata Kleinova,Heather Bender,Zdenek Andrysik,Joaquín M. Espinosa,Giulio Superti-Furga,Giulio Superti-Furga,Robin D. Dowell,Dylan J. Taatjes,Pavel Kovarik +18 more
TL;DR: CDK8 kinase activity promotes RNA polymerase II pause release in response to interferon-γ (IFN-γ), a universal cytokine involved in immunity and tumor surveillance and implicate CDK8 and CDK19 as essential for this transcriptional reprogramming.
References
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cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination
TL;DR: It is shown that stochastic gradient descent (SGD) and branch-and-bound maximum likelihood optimization algorithms permit the major steps in cryo-EM structure determination to be performed in hours or minutes on an inexpensive desktop computer.
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New tools for automated high-resolution cryo-EM structure determination in RELION-3.
Jasenko Zivanov,Takanori Nakane,Björn O. Forsberg,Dari Kimanius,Wim J. H. Hagen,Erik Lindahl,Erik Lindahl,Sjors H.W. Scheres +7 more
TL;DR: CPU-based vector acceleration has been added in addition to GPU support, which provides flexibility in use of resources and avoids memory limitations in the third major release of RELION.
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c-Myc regulates transcriptional pause release.
Peter B. Rahl,Charles Y. Lin,Amy C. Seila,Ryan A. Flynn,Scott McCuine,Christopher B. Burge,Phillip A. Sharp,Richard A. Young +7 more
TL;DR: It is reported that promoter-proximal pausing is a general feature of transcription by Pol II in mammalian cells and thus an additional step where regulation of gene expression occurs, and that the transcription factor c-Myc, a key regulator of cellular proliferation, plays a major role in Pol II pause release.
Journal ArticleDOI
Structural basis of transcription: RNA polymerase II at 2.8 angstrom resolution.
TL;DR: Structures of a 10-subunit yeast RNA polymerase II derived from two crystal forms at 2.8 and 3.1 angstrom resolution provide evidence for RNA exit in the vicinity of the carboxyl-terminal repeat domain, coupling synthesis to RNA processing by enzymes bound to this domain.
Journal ArticleDOI
Transcriptional Regulation and Its Misregulation in Disease
Tong Ihn Lee,Richard A. Young +1 more
TL;DR: Recent advances in understanding of transcriptional regulation are reviewed and how these have provided new insights into transcriptional misregulation in disease are discussed.
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