Active site opening and closure control translocation of multisubunit RNA polymerase
Open accessAbstract
Multisubunit RNA polymerase (RNAP) is the central information-processing enzyme in all cellular life forms, yet its mechanism of translocation along the DNA molecule remains conjectural. Here, we report direct monitoring of bacterial RNAP translocation following the addition of a single nucleotide. Time-resolved measurements demonstrated that translocation is delayed relative to nucleotide incorporation and occurs shortly after or concurrently with pyrophosphate release. An investigation of translocation equilibrium suggested that the strength of interactions between RNA 3' nucleotide and nucleophilic and substrate sites determines the translocation state of transcription elongation complexes, whereas active site opening and closure modulate the affinity of the substrate site, thereby favoring the post- and pre-translocated states, respectively. The RNAP translocation mechanism is exploited by the antibiotic tagetitoxin, which mimics pyrophosphate and induces backward translocation by closing the active site.
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The average elongation speed of RNAP on protein encoding genes is taken as 20 nt/s.
“since the average elongation speed of RNAP on protein encoding genes is taken as 20 nt/s.”
From Bringing the genetically minimal cell to life on a computer in 4D (2026) · cites this paper as [89]
The Introduction (page not specified in our copy) reports that E. coli RNAP moves at approximately 20–90 nt/s. It does not identify 20 nt/s as an average or specify that the rate applies to protein-encoding genes. (LLM, conf=0.86)
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“Translocation of the elongation complex (EC) along the DNA template, as well as entry and binding of the NTP substrate in the active site, is facilitated by an open active site with an unfolded TL (27).”
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Bringing the genetically minimal cell to life on a computer in 4D
Thornburg, Z. R., Maytin, A., Kwon, J., Brier, T. A., Gilbert, B. R., Fu, E., Gao, Y.-L., Quenneville, J., Wu, T., Li, H., et al. (2026) · Cell · doi:10.1016/j.cell.2026.02.009 · Cited by 44 · see citing works
DNA template sequence control of bacterial RNA polymerase escape from the promoter
Heyduk, E., & Heyduk, T. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky172 · Cited by 32 · see citing works
“(25) on ITS variants of T5 N25 promoter demonstrated a strong reverse correlation between escape efficiency and RNA sequence encoded bias for the pretranslocated state of RNAP enzyme (26,27).”
BackgroundMolecular basis of transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis
Xu, L., Da, L., Plouffe, S. W., Chong, J. P. C., Kool, E. T., & Wang, D. (2014) · DNA repair · doi:10.1016/j.dnarep.2014.03.024 · Cited by 32 · see citing works
Application of Markov State Models to Simulate Long Timescale Dynamics of Biological Macromolecules
Da, L., Sheong, F. K., Silva, D., & Huang, X. (2013) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-02970-2_2 · Cited by 36 · see citing works
“The interplays between the PPi release, TL opening motion and translocation have attracted extensive attentions [67, 68].”
BackgroundEsyunina, D., Turtola, M., Pupov, D., Bass, I., Klimašauskas, S., Belogurov, G. A., & Kulbachinskiy, A. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1521 · Cited by 30 · see citing works
“Folding and unfolding of the TL also modulates RNAP movement along the DNA because the intimate interactions of the folded TL with the 3′-end of the nascent RNA impede forward translocation (19,20).”
BackgroundInfluentialSelf-citationImashimizu, M., Shimamoto, N., Oshima, T., & Kashlev, M. (2014) · Transcription · doi:10.4161/trns.28285 · Cited by 30 · see citing works
“coli RNAP, the transition state involves PPi release, because it has been shown that a nucleotide addition precedes translocation and PPi release.(35) Below, we also discuss the case for pausing in the context of the power-stroke model.”
BackgroundTagetitoxin inhibits transcription by stabilizing pre-translocated state of the elongation complex
Yuzenkova, Y., Roghanian, M., Bochkareva, A., & Zenkin, N. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt708 · Cited by 30
“Therefore, TGT cannot actively shift the complex into the pre-translocated state, as was suggested earlier (6).”
BackgroundResultInfluentialJanissen, R., Eslami-Mossallam, B., Artsimovitch, I., Depken, M., & Dekker, N. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110749 · Cited by 29
“Recent cryo-EM structures of E. coli TECs stabilized in a paused state upon formation of an RNA hairpin (Guo et al., 2018; Kang et al., 2018) or by an engineered backtrack (Abdelkareem et al., 2019) confirmed these predictions.”
BackgroundInfluentialInterplay between the trigger loop and the F loop during RNA polymerase catalysis
Miropolskaya, N., Esyunina, D., Klimašauskas, S., Nikiforov, V., Artsimovitch, I., & Kulbachinskiy, A. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt877 · Cited by 29 · see citing works
“coli RNAP under similar conditions (30– 80 s 1 at 23–25 C) (18,28).”
BackgroundAn RNA-Based Theory of Natural Universal Computation.
Akhlaghpour, H. (2020) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2021.110984 · Cited by 28 · see citing works
Xu, L., Wang, W., Chong, J. P. C., Shin, J. H., Xu, J., & Wang, D. (2015) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2015.1087960 · Cited by 28 · see citing works
“stroke model), which in general occurs in longer timescales than PPi release (Malinen et al., 2012).”
BackgroundInfluentialColiphage HK022 Nun protein inhibits RNA polymerase translocation
Vitiello, C., Kireeva, M., Lubkowska, L., Kashlev, M., & Gottesman, M. (2014) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1319740111 · Cited by 26
“It has been shown recently that forward RNAP translocation is a rate-limiting step at some DNA sequences (7, 17, 39).”
BackgroundComputational Simulation Strategies for Analysis of Multisubunit RNA Polymerases
Wang, B., Feig, M., Cukier, R., & Burton, Z. (2013) · Chemical Reviews · doi:10.1021/cr400046x · Cited by 25 · see citing works
Geronimo, I., Vidossich, P., Donati, E., & Vivo, M. (2021) · WIREs Computational Molecular Science · doi:10.1002/wcms.1534 · Cited by 23 · see citing works
“In contrast to this system, RNA Pol II was simulated with the active site (i.e., trigger loop) already open prior to translocation 147 on the basis of earlier evidence from fluorescence 149 and MD simulation studies.”
MethodRNA polymerase stalls in a post-translocated register and can hyper-translocate
Nedialkov, Y. A., Nudler, E., & Burton, Z. (2012) · Transcription · doi:10.4161/trns.22307 · Cited by 23
Rate-limiting Pyrophosphate Release by HIV Reverse Transcriptase Improves Fidelity
Li, A., Gong, S., & Johnson, K. A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.753152 · Cited by 24 · see citing works
“(17) monitored RNA polymerase (RNAP) translocation along its DNA substrate using fluorescent base analogs and revealed fast translocation rates after incorporation of various nucleotides, with half-lives (t1⁄2) between 7 and 12 ms.”
BackgroundNanobiology of RNA Polymerase: Biological Consequence of Inhomogeneity in Reactant
Shimamoto, N. (2013) · Chemical Reviews · doi:10.1021/cr400006b · Cited by 20 · see citing works
Kireeva, M., Trang, C., Matevosyan, G., Turek-Herman, J., Chasov, V., Lubkowska, L., & Kashlev, M. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky393 · Cited by 19 · see citing works
“However, the Brownian ratchet model of translocation did not explain well the results of the pre-steady-state analyses of transcription elongation, which were more consistent with a slow and poorly reversible translocation (10,24,26,34).”
BackgroundResultInfluentialRNA Polymerase II Activity Control of Gene Expression and Involvement in Disease
Kuldell, J. C., & Kaplan, C. D. (2024) · Journal of Molecular Biology · doi:10.1016/j.jmb.2024.168770 · Cited by 15 · see citing works
The mechanism of the nucleo-sugar selection by multi-subunit RNA polymerases
Mäkinen, J., Shin, Y., Vieras, E., Virta, P., Metsä‐Ketelä, M., Murakami, K. S., & Belogurov, G. A. (2021) · Nature Communications · doi:10.1038/s41467-021-21005-w · Cited by 16 · see citing works
Self-citationPyrophosphate Release in the Protein HIV Reverse Transcriptase
Atis, M., Johnson, K., & Elber, R. (2017) · Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.7b08320 · Cited by 16
Skancke, J., Bar, N., Kuiper, M., & Hsu, L.-L. M. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b00272 · Cited by 15 · see citing works
Bao, Y., & Landick, R. (2021) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1101/2021.01.27.428476 · Cited by 14
“The slightly higher SPB of dA20 EC versus A20 EC is consistent with prior observations that a 3′ deoxy substitution favors the pretranslocated register, which favors TL folding (45).”
BackgroundResultOxazinomycin arrests RNA polymerase at the polythymidine sequences
Prajapati, R. K., Rosenqvist, P., Palmu, K., Mäkinen, J., Malinen, A. M., Virta, P., Metsä‐Ketelä, M., & Belogurov, G. A. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz782 · Cited by 16 · see citing works
Self-citationShin, Y., Hedglin, M., & Murakami, K. (2019) · bioRxiv · doi:10.1093/nar/gkz1221 · Cited by 12 · see citing works
“2-AP displays weak and strong fluorescence signals when it stacked and unstacked with neighboring bases, respectively (Figure 2B and Supplementary Figure S5) (31,32).”
BackgroundActive site closure stabilizes the backtracked state of RNA polymerase
Turtola, M., Mäkinen, J. J., & Belogurov, G. A. (2018) · bioRxiv · doi:10.1093/nar/gky883 · Cited by 12 · see citing works
“Backtracking by many nucleotides extrudes the unpaired nucleotides into the secondary channel of RNAP (Cheung & Cramer, 2011), a route for NTP substrate entry into the active site.”
BackgroundInfluentialSelf-citationA structure-based kinetic model of transcription
Zuo, Y., & Steitz, T. (2016) · Transcription · doi:10.1080/21541264.2016.1234821 · Cited by 12 · see citing works
The phosphate ester group in secondary metabolites.
Della-Felice, F., Bartolomeu, A. D. A., & Pilli, R. (2022) · Natural product reports (Print) · doi:10.1039/d1np00078k · Cited by 11 · see citing works
Foster, P., Niccum, B. A., & Lee, H. (2021) · bioRxiv · doi:10.1128/mbio.02503-21 · Cited by 9
“In Escherichia coli replication proceeds at an average of 650 bp/s (1), whereas transcription, at its fastest, proceeds at about a tenth of this speed (2).”
BackgroundTranslocation and fidelity of Escherichia coli RNA polymerase
Nedialkov, Y. A., & Burton, Z. (2013) · Transcription · doi:10.4161/trns.25527 · Cited by 9
“As previously indicated, these data also strongly support the previous model that the RNAP TEC rests in a primarily post-translocated state.(1,2) Conditions can be found that stabilize what we interpret as a post-translocated TEC (C50 and C49 DNA bands; exo III digestion to i+19 and i+18),(2) in the presence of CTP, e…”
InfluentialKing, J. J., & Larijani, M. (2020) · FEBS Letters · doi:10.1002/1873-3468.13962 · Cited by 8
Functional assays for transcription mechanisms in high-throughput
Qiu, C., & Kaplan, C. D. (2019) · Methods · doi:10.1016/j.ymeth.2019.02.017 · Cited by 8 · see citing works
Unveiling translocation intermediates of RNA polymerase
Imashimizu, M., & Kashlev, M. (2014) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1406413111 · Cited by 8
Malinen, A., Turtola, M., & Belogurov, G. A. (2015) · Methods in molecular biology · doi:10.1007/978-1-4939-2392-2_3 · Cited by 8
Self-citationDutagaci, B., Duan, B., Qiu, C., Kaplan, C. D., & Feig, M. (2023) · PLOS Computational Biology · doi:10.1371/journal.pcbi.1010999 · Cited by 7 · see citing works
“69 The TL has open and closed conformations, which are known to be important for the nucleotide 70 addition (10-13).”
BackgroundWang, C.-N., Masuda, Y., & Senoo, K. (2025) · Microorganisms · doi:10.3390/microorganisms13071448 · Cited by 7
Dynamics of bridge helix bending in RNA polymerase II
Wang, Z.-F., Fu, Y.-B., Wang, P.-Y., & Xie, P. (2017) · Proteins: Structure, Function, and Bioinformatics · doi:10.1002/prot.25239 · Cited by 6 · see citing works
Pardo-Avila, F., Da, L.-T., Wang, Y., & Huang, X.-H. (2013) · Journal of Theoretical and Computational Chemistry · doi:10.1142/s0219633613410058 · Cited by 5 · see citing works
Wang, Q., Xu, Y.-Q., Gu, Z., Liu, N., Jin, K., Li, Y., Crabbe, M., & Zhong, Y. (2017) · Comput. Biol. Chem. · doi:10.1016/j.compbiolchem.2017.11.002 · Cited by 4 · see citing works
“Many medical inhibitors including rifampicin, tagetitoxin and myxopyronin specifically target rpoB and rpoC subunits of the RNAP enzyme (Artsimovitch et al., 2011; Malinen et al., 2012; Mukhopadhyay et al., 2008).”
BackgroundResponse to Klyuyev and Vassylyev: On the mechanism of tagetitoxin inhibition of transcription
Svetlov, V., Artsimovitch, I., & Nudler, E. (2012) · Transcription · doi:10.4161/trns.19749 · Cited by 4 · see citing works
Dulin, D., Bauer, D. L. V., Malinen, A., Bakermans, J. J. W., Kaller, M., Morichaud, Z., Petushkov, I., Depken, M., Brodolin, K., Kulbachinskiy, A., et al. (2017) · Nature Communications · doi:10.1038/s41467-018-03902-9 · Cited by 3 · see citing works
Self-citationRole of the trigger loop in translesion RNA synthesis by bacterial RNA polymerase
Agapov, A., Ignatov, A., Turtola, M., Belogurov, G. A., Esyunina, D., & Kulbachinskiy, A. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.011844 · Cited by 3 · see citing works
“Furthermore, the same fluorescence intensity was observed after the extension of the TEC with 2’dGMP, which promotes forward translocation because the 29-OH group at the RNA 39-end is essential for stabilizing the pretranslocated state (52).”
BackgroundResultSelf-citationHwang, C. S., Xu, L., Wang, W., Ulrich, S., Zhang, L., Chong, J., Shin, J. H., Huang, X.-H., Kool, E., McKenna, C., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw220 · Cited by 3
Johnson, R. S., Strausbauch, M., & McCloud, C. (2022) · PLoS ONE · doi:10.1371/journal.pone.0273746 · Cited by 2
Janissen, R., Eslami-Mossallam, B., Artsimovitch, I., Depken, M., & Dekker, N. (2019) · doi:10.1101/762468 · Cited by 2
“The inability of the BH and TL to fold correctly to the cleavage-competent conformations is thought to sterically hinder the backtracked RNA transcript, delaying cleavage and stabilizing the backtracked TEC in a ratcheted confomation.(30,34,61,66,74) The resistance to GreB-assisted cleavage and the significantly decre…”
Structural dynamics of RNA polymerase II throughout the nucleotide addition cycle
Yi, G., Li, Q.-R., Holmberg, H., Li, S.-S., Clare, D., Wang, D., & Zhang, P.-J. (2026) · Nature Communications · doi:10.1038/s41467-026-75257-5 · Cited by 1
Genomic and mutational analysis of Pseudomonas syringae pv. tagetis EB037 pathogenicity on sunflower
Maul, J. E., Lydon, J., Lakshman, D., Willard, C., Kong, H., & Roberts, D. P. (2025) · BMC Microbiology · doi:10.1186/s12866-024-03685-8 · Cited by 1
Higher-order epistasis within Pol II trigger loop haplotypes
Duan, B., Qiu, C., Lockless, S. W., Sze, S., & Kaplan, C. D. (2024) · Genetics · doi:10.1093/genetics/iyae172 · Cited by 1 · see citing works
“Pol II transcribes eukaryotic DNA into RNA using an iterative nucleotide addition cycle (NAC) (Bar-Nahum et al. 2005; Wang et al. 2006b; Malinen et al. 2012; Dangkulwanich et al. 2013; Kaplan 2013; Kuldell and Kaplan 2024).”
Probing the nucleobase selectivity of RNA polymerases with dual-coding substrates
Mäkinen, J., Rosenqvist, P., Virta, P., Metsä‐Ketelä, M., & Belogurov, G. A. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107755 · Cited by 1 · see citing works
“When supplied with three canonical NTPs and tri-phosphorylated nucleoside analogs, RNAPs transcribed further than with three canonical NTPs in several cases.”
InfluentialSelf-citationWidespread epistasis shapes RNA polymerase II active site function and evolution
Duan, B., Qiu, C., Sze, S., & Kaplan, C. D. (2025) · Nature Communications · doi:10.1038/s41467-025-63304-6 · Cited by 4 · see citing works
“During each NAC, the TL nucleotide interaction region (NIR) discriminates correct NTPs from mismatched ones, initiating a shift from a catalytic-disfavoring “ open ” state to a catalytic-favoring “ closed ” state 11,20,29,30 .”
Structural Dynamics of RNA Polymerase II During Nucleotide Addition Cycle
Yi, G., Li, Q.-R., Holmberg, H., Li, S.-S., Clare, D., Wang, D., & Zhang, P.-J. (2026) · bioRxiv · doi:10.64898/2026.06.04.730248
Hsu, L.-L. M., & Han, N. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110610
“RNAP, RNA polymerase; TEC, ternary elongation complex. the pretranslocated state when the RNA 3 ′ dinucleotides are pyrimidines (26–28).”
Higher-order epistasis within Pol II trigger loop haplotypes
Duan, B.-B., Qiu, C.-X., Lockless, S. W., Sze, S.-H., & Kaplan, C. (2024) · bioRxiv · doi:10.1101/2024.01.20.576280
Braffman, N., Hauver, J., Campbell, E., & Darst, S. (2019) · doi:10.2210/pdb6n60/pdb
- Authors
- Malinen, A. M., Turtola, M., Parthiban, M., Vainonen, L., Johnson, M. S., & Belogurov, G. A.
- Affiliations
- Åbo Akademi University (FI)
- Department of Biochemistry and Food Chemistry, University of Turku, 20014, Turku, Finland and 2Biochemistry, Department of Biosciences, Åbo Akademi University, Tykistökatu 6A, 20520 Turku, Finland
- Corresponding author
- Belogurov, Georgiy A.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-05-08
- Volume
- 40
- Issue
- 15
- Pages
- 7442-7451
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC3424550
- OpenAlex
- W2157844474
- Cited by
- 90
- References
- 48
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 9 · 2018: 6 · 2017: 6 · 2016: 10 · 2015: 6 · 2014: 8 · 2013: 12 · 2012: 7
- FWCI
- 4.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Åbo Akademi University Research Portal (submittedVersion)
- Funders
- Biocenter Finland
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- translocation mechanism, transcription elongation complex, pyrophosphate release, nucleotide incorporation, antibiotic mechanism of action, bacterial RNA polymerase, time-resolved measurement
- MeSH terms
- Bacteria, Dicarboxylic Acids, DNA, Enzyme Inhibitors, Fluorescent Dyes, Nucleotides, Organophosphorus Compounds, Diphosphates, RNA, DNA-Directed RNA Polymerases, Transcription, Genetic, Catalytic Domain, Protein Subunits, Protein Transport
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