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Structural Basis of Transcription Initiation by RNA Polymerase II

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FOCUS ON TRAnscRIPTIon REVIEWS Structural basis of transcription initiation by RNA polymerase II Sarah Sainsbury*, Carrie Bernecky* and Patrick Cramer Abstract | Transcription of eukaryotic protein-coding genes commences with the assembly of a conserved initiation complex, which consists of RNA polymerase II (Pol II) and the general transcr­iption factors, at promoter DNA. After two decades of research, the structural basis of transcription initiation is emerging. Crystal structures of many components of the initiation complex have been resolved, and structural information on Pol II complexes with general transcription factors has recently been obtained. Although mechanistic details await elucidation, available data outline how Pol II cooperates with the general transcription factors to bind to and open promoter DNA, and how Pol II directs RNA synthesis and escapes from the promoter. Transcription of the eukaryotic genome is carried In the classical model, a Pol II–TFIIF complex binds out by nuclear RNA polymerase I (Pol I), Pol II and to a pre-formed TFIIB–TBP–DNA promoter complex, Pol III. Whereas Pol I transcribes the rRNA precur- resulting in the formation of a core initiation complex sor, Pol III transcribes small non-coding RNAs such as (FIG. 1). The core initiation complex is conserved in the tRNAs. Pol II is a 12‑subunit enzyme that transcribes Pol I and Pol III transcription systems, which also use TBP protein-coding genes to produce mRNAs. Pol II regu- and contain proteins with homologies to TFIIB and TFIIF lation underlies cell differentiation, the maintenance of (reviewed in REF. 7). The core initiation complex binds to cell identity and the responses of cells to environmen- TFIIE and TFIIH to form a complete PIC that contains tal changes. It occurs at different stages of transcrip- closed, double-stranded promoter DNA (TABLE 1). In the tion, although regulation at the stage of initiation is presence of nucleoside triphosphates, a central DNA a key mechanism for the control of gene expression. region is melted, leading to a ‘transcription bubble’ and Understanding Pol II regulation, therefore, requires the formation of the open promoter complex. In the open detailed insights into the structure of the Pol II ini- promoter complex, the DNA template strand passes near tiation complex and the molecular mechanisms of the Pol II active site and can programme DNA-templated transcriptio­n initiation. RNA chain synthesis. Most general transcription fac- For initiation, Pol II assembles with the general tors are modular and contain structured domains that transcription factors TFIIB, TFIID, TFIIE, TFIIF are connected by flexible linkers. Upon assembly of the and TFIIH, which are collectively known as the gen- PIC, these factors adopt their functional structure. Their eral transcription factors, at promoter DNA to form linker regions fold on the Pol II surface, and their protein the pre-initiation complex (PIC) (TABLE 1). According domains locate to sites where they can exhibit specialized to exemplary studies with a subset of promoters, the functions. Detailed structural information on how gen- Max Planck Institute for general transcription factors cooperate with Pol II to eral factors interact with Pol II is scarce, but recent studies Biophysical Chemistry, bind to and open promoter DNA, and to initiate RNA have increased our understandin­g of the 3D architecture Department of Molecular synthesis and stimulate the escape of Pol II from the of initiatio­n complexes8–13. Biology, Am Fassberg 11, 37077 Göttingen, Germany. promoter. TFIID contains the TATA box-binding pro- In this Review, we summarize known structural *These authors contributed tein (TBP) and several TBP-associated factors (TAFs). information on Pol II initiation complexes and discuss equally to this work. Whereas TBP is required for transcription from all the functions of PIC components. We describe available Correspondence to P.C. promoters, the TAFs have promoter-specific func- structures for the general transcription factors and their e-mail: patrick.cramer@ tions. Order‑of‑addition experiments1 combined with complexes (TABLE 2; see Supplementary information S1 mpibpc.mpg.de doi:10.1038/nrm3952 in vivo analysis led to the classical model of stepwise PIC (table)), following the order of the stepwise assembly Published online assembly (reviewed in REFS 2–6), although alternative model of PIC formation. We start with the recruitment 18 February 2015 assembly pathways are possible. of initiation factors to promoter DNA, the formation of NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 16 | MARCH 2015 | 129 © 2015 Macmillan Publishers Limited. All rights reserved REVIEWS Table 1 | Subunits of Pol II and general transcription factors Factor Gene name Mass (kDa) Uniprot accession number Copies Yeast Human Yeast Human Yeast Human Pol II (RNAP*): transcribing enzyme RPB1 RPO21 POLR2A 191.6 217.2 P04050 P24928 1 RPB2 RPB2 POLR2B 138.8 133.9 P08518 P30876 1 RPB3 RPB3 POLR2C 35.3 31.4 P16370 P19387 1 RPB4 RPB4 POLR2D 25.4 16.3 P20433 O15514 1 RPB5‡ RPB5 POLR2E 25.1 24.6 P20434 P19388 1 RPB6‡ RPO26 POLR2F 17.9 14.5 P20435 P61218 1 RPB7 RPB7 POLR2G 19.1 19.3 P34087 P62487 1 RPB8‡ RPB8 POLR2H 16.5 17.1 P20436 P52434 1 RPB9 RPB9 POLR2I 14.3 14.5 P27999 P36954 1 RPB10‡ RPB10 POLR2L 8.3 7.6 P22139 P62875 1 RPB11 RPB11 POLR2J 13.6 13.3 P38902 P52435 1 RPB12‡ RPB12 POLR2K 7.7 7.0 P40422 P53803 1 Total 513.6 516.7 (12 subunits) TFIIA§: TBP stabilization and counteracts repressive effects of negative co‑factors Large subunit TOA1 GTF2A1 32.2 41.5 P32773 P52655 1 Small subunit TOA2 GTF2A2 13.5 12.5 P32774 P52657 1 Total 45.7 54.0 (2 subunits) TFIIB: Pol II recruitment, TBP binding and TSS selection TFIIB (TFB*) SUA7 GTF2B 38.2 34.8 P29055 Q00403 1 TFIID: Pol II recruitment and promoter recognition TBP (TBP*): recognition TBP TBP 27.0 37.7 P13393 P20226 1 of the TATA box TAF1 TAF1 TAF1 120.7 212.7 P46677 P21675 1 TAF2 TAF2 TAF2 161.5 137.0 P23255 Q6P1X5 1 TAF3 TAF3 TAF3 40.3 103.6 Q12297 Q5VWG9 1 TAF4 TAF4 TAF4 42.3 110.1 P50105 O00268 2 TAF5 TAF5 TAF5 89.0 86.8 P38129 Q15542 2 TAF6 TAF6 TAF6 57.9 72.7 P53040 P49848 2 TAF7 TAF7 TAF7 67.6 40.3 Q05021 Q15545 1 TAF8 TAF8 TAF8 58.0 34.3 Q03750 Q7Z7C8 1 TAF9 TAF9 TAF9 17.3 29.0 Q05027 Q16594 2 TAF10 TAF10 TAF10 23.0 21.7 Q12030 Q12962 2 TAF11 TAF11 TAF11 40.6 23.3 Q04226 Q15544 1 TAF12 TAF12 TAF12 61.1 17.9 Q03761 Q16514 2 TAF13 TAF13 TAF13 19.1 14.3 P11747 Q15543 1 TAF14|| TAF14 NA 27.4 NA P35189 NA 3 Total 1,200¶ 1,300¶ (14–15 subunits) TFIIE: recruitment of TFIIH and open DNA stabilization TFIIEα (TFE*) TFA1 GTF2E1 54.7 49.5 P36100 P29083 1 TFIIEβ TFA2 GTF2E2 37.0 33.0 P36145 P29084 1 Total 91.7 82.5 (2 subunits) 130 | MARCH 2015 | VOLUME 16 www.nature.com/reviews/molcellbio © 2015 Macmillan Publishers Limited. All rights reserved FOCUS ON TRAnscREVIEWSRIPTIon Table 1 (cont.) | Subunits of Pol II and general transcription factors Factor Gene name Mass (kDa) Uniprot accession number Copies Yeast Human Yeast Human Yeast Human TFIIF§: TSS selection and stabilization of TFIIB TFIIFα TFG1 GTF2F1 82.2 58.2 P41895 P35269 1 TFIIFβ TFG2 GTF2F2 46.6 28.4 P41896 P13984 1 TFG3# TAF14 NA 27.4 NA P35189 NA NA Total 156.2 86.6 (2–3 subunits) TFIIH§ (core): promoter opening and DNA repair Subunit 1 (p62) TFB1 GTF2H1 72.9 62.0 P32776 P32780 1 Subunit 2 (p44) SSL1 GTF2H2 52.3 44.4 Q04673 Q13888 1 Subunit 3 (p34) TFB4 GTF2H3 37.5 34.4 Q12004 Q13889 1 Subunit 4 (p52) TFB2 GTF2H4 58.5 52.2 Q02939 Q92759 1 Subunit 5 (p8) TFB5 GTF2H5 8.2 8.1 Q3E7C1 Q6ZYL4 1 XPD subunit: ATPase; RAD3 ERCC2 89.8 86.9 P06839 P18074 1 DNA repair XPB subunit: ATPase; SSL2 ERCC3 95.3 89.3 Q00578 P19447 1 promoter opening Total 414.5 377.3 (7 subunits) TFIIH (kinase module): CTD phosphorylation Cyclin H CCL1 CCNH 45.2 37.6 P37366 P51946 1 CDK7 KIN28 CDK7 35.2 39.0 P06242 P50613 1 MAT1 TFB3 MNAT1 38.1 35.8 Q03290 P51948 1 Total 118.5 112.4 (3 subunits) CTD, C‑terminal domain; NA, not available; Pol, RNA polymerase; TAF, TBP-associated factor; TBP, TATA-box-binding protein; TFIIA, transcription initiation factor IIA; TSS, transcription start site. *Archaeal homologue. ‡Factor shared between Pol I, Pol II and Pol III. §No known archaeal homologue. ||Component of TFIID, TFIIF and chromatin remodelling complexes. ¶Approximate molecular weight. #TFG3 is a component of TFIID, TFIIF and chromatin remodelling complexes; the yeast-specific subunit is non-essential as part of TFIIF and as part of TFIID212. the core initiation complex and the interaction of this TFIIB was found to be located on the Pol II dock domain complex with the auxiliary factor TFIIA. We then dis- using biochemical probing26 and X‑ray crystallography27 cuss TFIIE and TFIIH and their roles in promoter DNA (BOX 1). As this domain was not present in the TFIIB– opening. Finally, we discuss how recent data on the TBP–DNA complex structure19, a model for the Pol II– structure of TFIID provide insights into its functions in TFIIB–TBP–DNA complex had to be derived with the determinin­g promoter specificity. use of site-specific protein cleavage probing28,29 (BOX 1). In 2009, the structure of the complete 12‑subunit A brief history of initiation complex architecture Pol II bound by TFIIB confirmed the location of the Structural analyses of the PIC started over two decades B‑ribbon domain on the dock and positioned one of ago.
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    Tyr1 Phosphorylation Promotes Phosphorylation of Ser2 on the C-Terminal Domain

    1 Tyr1 phosphorylation promotes phosphorylation of Ser2 on the C-terminal domain 2 of eukaryotic RNA polymerase II by P-TEFb 3 Joshua E. Mayfield1† *, Seema Irani2*, Edwin E. Escobar3, Zhao Zhang4, Nathanial T. 4 Burkholder1, Michelle R. Robinson3, M. Rachel Mehaffey3, Sarah N. Sipe3,Wanjie Yang1, 5 Nicholas A. Prescott1, Karan R. Kathuria1, Zhijie Liu4, Jennifer S. Brodbelt3, Yan Zhang1,5 6 1 Department of Molecular Biosciences, 2Department of Chemical Engineering, 7 3 Department of Chemistry and 5 Institute for Cellular and Molecular Biology, University of 8 Texas, Austin 9 4 Department of Molecular Medicine, Institute of Biotechnology, University of Texas 10 Health Science Center at San Antonio 11 †Current Address: Department of Pharmacology, University of California, San Diego, La 12 Jolla 13 * These authors contributed equally to this paper. 14 Correspondence: Yan Zhang ([email protected]) 15 16 1 17 Summary 18 The Positive Transcription Elongation Factor b (P-TEFb) phosphorylates 19 Ser2 residues of C-terminal domain (CTD) of the largest subunit (RPB1) of RNA 20 polymerase II and is essential for the transition from transcription initiation to 21 elongation in vivo. Surprisingly, P-TEFb exhibits Ser5 phosphorylation activity in 22 vitro. The mechanism garnering Ser2 specificity to P-TEFb remains elusive and 23 hinders understanding of the transition from transcription initiation to elongation. 24 Through in vitro reconstruction of CTD phosphorylation, mass spectrometry 25 analysis, and chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we 26 uncover a mechanism by which Tyr1 phosphorylation directs the kinase activity of 27 P-TEFb and alters its specificity from Ser5 to Ser2.