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Structural insights into transcriptional regulation of human RNA polymerase III

Nature Structural & Molecular Biology volume 28, pages 220–227 (2021)Cite this article

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Abstract

RNA polymerase III (Pol III) synthesizes structured, essential small RNAs, such as transfer RNA, 5S ribosomal RNA and U6 small nuclear RNA. Pol III, the largest nuclear RNA polymerase, is composed of a conserved core region and eight constitutive regulatory subunits, but how these factors jointly regulate Pol III transcription remains unclear. Here, we present cryo-EM structures of human Pol III in both apo and elongating states, which unveil both an orchestrated movement during the apo-to-elongating transition and an unexpected apo state in which the RPC7 subunit tail occupies the DNA–RNA-binding cleft of Pol III, suggesting that RPC7 plays important roles in both autoinhibition and transcription initiation. The structures also reveal a proofreading mechanism for the TFIIS-like subunit RPC10, which stably retains its catalytic position in the secondary channel, explaining the high fidelity of Pol III transcription. Our work provides an integrated picture of the mechanism of Pol III transcription regulation.

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Fig. 1: Overall structures of the apo and EC structures of human Pol III.
Fig. 2: Modular movements of Pol III and the RPC3–RPC6–RPC7 heterotrimer.
Fig. 3: The C-terminal tail of RPC7 acts as a negative regulator of Pol III.
Fig. 4: The C-terminal Zn-ribbon motif of RPC10 stably locates in the secondary channel in both apo and transcribing Pol III.
Fig. 5: A proposed schematic model of Pol III transcriptional regulation.

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Data availability

The cryo-EM 3D maps of human Pol III in the apo form and in complex with the scaffold have been deposited in the EMDB database with accession codes EMD-30578 and EMD-30577, respectively. The atomic models of human Pol III in the apo form and in complex with the scaffold have been deposited in the PDB database with accession codes 7D59 and 7D58, respectively. Source data are provided with this paper.

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Acknowledgements

We thank the staff members of the Electron Microscopy Facility and Mass Spectrometry Facility at the Shanghai Institute of Precision Medicine for providing technical support and assistance with data collection. This work was supported by grants from the National Key R&D Program of China (2018YFA0107000 to M.L.), the National Natural Science Foundation of China (31525007 and 31930063 to M.L., 31900929 and U1932114 to P.L., 31900855 to Q.W., 81902085 to Y.X.), the Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20181711 to J.W.), the Shanghai Pujiang Program (19PJ1407200 to Q.W.), the Innovative Research Team of High-level Local University in Shanghai (SSMU-ZDCX20180702 to Q.W., SSMU-ZDCX20180401 to P.L.) and the Fund of Excellent Young Scholars of Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine (to P.L.).

Author information

Author notes

  1. These authors contributed equally: Qianmin Wang, Shaobai Li, Futang Wan, Youwei Xu.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Qianmin Wang, Shaobai Li, Futang Wan, Zhenfang Wu, Mi Cao, Pengfei Lan, Ming Lei & Jian Wu

  2. Shanghai Institute of Precision Medicine, Shanghai, China

    Qianmin Wang, Shaobai Li, Futang Wan, Zhenfang Wu, Mi Cao, Pengfei Lan, Ming Lei & Jian Wu

  3. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China

    Youwei Xu

  4. Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Ming Lei

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Contributions

Q.W. and F.W. purified the human Pol III complex. Q.W., F.W., M.C. and S.L. prepared cryo-EM specimens, collected datasets and determined the structure. J.W. and Y.X. carried out model building and refinement. Z.W. and F.W. carried out yeast functional analysis. All authors contributed to data interpretation and the writing of the manuscript. M.L., Q.W. and P.L. wrote the manuscript. M.L., Q.W. and J.W. initiated and orchestrated the project.

Corresponding authors

Correspondence to Pengfei Lan, Ming Lei or Jian Wu.

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The authors declare no competing interests.

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Peer review information Nature Structural & Molecular Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available. Beth Moorefield was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Extended data

Extended Data Fig. 1 Domain organization of all 17 subunits of human Pol III.

Black lines above the domain bar denote the modeled regions with clear EM densities.

Extended Data Fig. 2 Purification and characterization of human Pol III.

a, SDS-PAGE analysis of the purified human Pol III by silver staining. b, A representative negative−staining image of human Pol III. c, 2D class average views of the negative-staining images of human Pol III. Uncropped image for panel a is available as source data.

Source data

Extended Data Fig. 3 Cryo-EM analysis of human Pol III EC.

a, Left: A representative raw cryo-EM image of human Pol III EC. Right: 2D class average views of human Pol III EC. b, Image processing flowchart for human Pol III EC. c, Local resolution map for human Pol III EC. d, Angular distribution of particles for final reconstruction of human Pol III EC. e, Fourier Shell Correlation curve of constructed map of human Pol III EC.

Extended Data Fig. 4 Cryo-EM density maps of human Pol III EC and the active center.

a, Cryo-EM density map of human Pol III EC is shown in two different views. Protein subunits and the DNA-RNA scaffold are color coded as in Fig. 1b. b, Representative cryo-EM density maps for the selected elements of the human Pol III protein subunits. c, Close-up views of the active center of bacterial RNA polymerase (PDB: 2o5i), bovine Pol II (PDB: 5flm), yeast Pol I (PDB: 5m3f) and human Pol III. The lid loop, the fork loop 1 and the rudder are colored in yellow, magenta and blue, respectively.

Extended Data Fig. 5 Cryo-EM analysis of apo human Pol III.

a, Left: A representative raw cryo-EM image of the apo human Pol III. Right: 2D class average views of apo human Pol III. b, Image processing flowchart for apo human Pol III. The data processing details are described in the method session. c, Local resolution map for apo human Pol III. d, Angular distribution of particles for final reconstruction of apo human Pol III. e, Fourier Shell Correlation curve of constructed map of apo human Pol III.

Extended Data Fig. 6 Cryo-EM density maps of apo human Pol III.

a, Cryo-EM density map of the apo human Pol III complex is displayed in two different views. Protein subunits are color coded as in Fig. 1b. b, Cryo-EM density map of human Pol III in transcribing state with endogenous DNA in the catalytic cleft. The Pol III EC structure was fit into the density map (semi-transparent). The density corresponding to the double-stranded DNA is highlighted in yellow.

Extended Data Fig. 7 Structural comparison of the yeast and human RPC6 C-terminus and the location of WH domains 1 and 2 of RPC5 in human Pol III.

a, Multiple sequence alignment of the C-terminus of RPC6 from representative species reveals that yeast Pol III lacks the [4Fe-4S]-binding motif (Homo sapiens; Pan troglodytes; Mus musculus; Rattus norvegicus; Sus scrofa; Bos taurus; Xenopus laevis; Danio rerio and Saccharomyces cerevisiae). Four cystine residues in the [4Fe-4S]-binding motif are highlighted by red magenta arrow heads. b, Close-up comparison of the C-terminus of C34 and RPC6 in human (left) and yeast (right) Pol III structures, respectively. c, Left: Cryo-EM density map of apo Pol III with focused mask refinement for RPC5 WH domains 1 and 2. Right: Pol III EC at a lower threshold for visualization of RPC5 WH domains 1 and 2.

Extended Data Fig. 8 Multiple sequence alignment RPC7, BRF1, RPC10 and RPC1.

a, Multiple sequence alignment of the stalk-interaction motif of RPC7 from representative species. b, Multiple sequence alignment of RPC7CT. Two observed regions of RPC7CT in the EM density map are highlighted in red and magentas boxes, respectively. Two regions of RPC7CT analyzed by yeast tetrad analysis are highlighted in the blue box and cyan arrowheads, respectively. c, Multiple sequence alignment of the N-terminal Zn-ribbon motif of BRF1. Amino acids involved in the contact with RPC7CT are highlighted in blue box. d, Multiple sequence alignment of the anchor region of RPC10. RPC10 Leu53 is highlighted by a gold arrowhead. e, Multiple sequence alignment of the RPC10-anchor-interacting region of RPC1. Amino acids involved in the hydrophobic interactions with the RPC10 anchor around RPC10Leu35 are highlighted in green arrowheads.

Extended Data Fig. 9 Superposition analysis of the C-Zn-ribbon motif of RPC10 in human Pol III and TFIIS in yeast backtracked Pol II.

a, Superposition of the C-Zn-ribbon motif of RPC10 in human Pol III elongation complex (orange) and TFIIS in yeast backtracked Pol II structures containing mismatched DNA-RNA hybrid (3po3 and 3gtm in cyan and gray, respectively). b, Top: Close-up view of the C-Zn-ribbon motif of RPC10 modeled onto yeast Pol II backtracked DNA-RNA hybrid (3gtm). Bottom: Close-up view of the C-Zn-ribbon motif of TFIIS in yeast backtracked Pol II (3gtm).

Extended Data Fig. 10 Superimposition of yeast Maf1 with human Pol III.

Structure of yeast Maf1 (PDB:6tut) modeled onto the apo structure of human Pol III in two views reveals that MAF1 binding is not compatible with the autoinhibited state of Pol III.

Supplementary information

Supplementary Information

Supplementary Table 1.

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Supplementary Video 1

A movie of human Pol III with structural information of the RPC7 C terminus, the [4Fe–4S], the transition between the apo and EC states of Pol III, as well as the constant surveillance factor RPC10.

Source data

Source Data Fig. 2

Unprocessed images of yeast growth on plates.

Source Data Fig. 3

Unprocessed images of yeast growth on plates.

Source Data Extended Data Fig. 2

Unprocessed SDS–PAGE gel.

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Wang, Q., Li, S., Wan, F. et al. Structural insights into transcriptional regulation of human RNA polymerase III. Nat Struct Mol Biol 28, 220–227 (2021). https://doi.org/10.1038/s41594-021-00557-x

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