Sequential verification of transcription by Integrator and Restrictor
Open accessAbstract
The decision between productive elongation and premature termination of promoter-proximal RNA polymerase II (RNAPII) is fundamental to metazoan gene regulation. Integrator and Restrictor complexes are implicated in promoter-proximal termination, but why metazoans utilize two complexes and how they are coordinated remains unknown. Here, we show that Integrator and Restrictor act sequentially to monitor distinct stages of transcription. Integrator predominantly engages with promoter-proximally paused RNAPII to trigger premature termination, which is prevented by cyclin-dependent kinase 7/9 activity. After pause release, RNAPII enters a "restriction zone"-universally imposed by Restrictor. Unproductive RNAPII terminates within this zone, while progression through it is promoted by U1 small nuclear ribonucleoprotein particles (snRNPs), which antagonize Integrator and Restrictor in a U1-70K-dependent manner. These findings reveal the principles of a sequential verification mechanism governing the balance between productive and attenuated transcription, rationalizing the necessity of Integrator and Restrictor complexes in metazoans.
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The Integrator complex plays a role in premature RNA Polymerase II transcription termination of mRNAs and in processing of other small RNAs through mechanisms that require the RNA exosome.
“The Integrator complex is known to play a role in premature RNA Polymerase II transcription termination of mRNAs in addition to processing of other small RNAs through mechanisms that require the RNA exosome85–87.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [86]
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Zytnicki, M., & González, I. (2021) · PLoS ONE · doi:10.1371/journal.pone.0256196 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Coordinating mRNA maturation: The U1 relay model
Yoon, Y., Quan, C., Soles, L. V., & Shi, Y. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.01.006 · Cited by 8 · see citing works
The Promoter-Proximal Pause: A Decision Point Governing RNA Polymerase II Fate
Hyder, U., & Bentley, D. L. (2026) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-051424-053703 · Cited by 4 · see citing works
Jiang, S., Jia, Z., Zhu, W., Liu, Y., Fu, H., Zhu, F., Li, Z., Yang, J., Zhu, Y., Sun, Z., et al. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.01.015 · Cited by 3 · see citing works
Sequence-specific RNA recognition drives Restrictor-mediated termination of extragenic transcription
Polizzese, D., Mandana, G. M., Russo, M., Polletti, S., Prosperini, E., Ciossani, G., Monzani, S., Scietti, L., Rodighiero, S., Gualdrini, F., et al. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.02.006 · Cited by 2 · see citing works
Regulation of RNA transcript elongation in metazoans and its relevance to disease
Mimoso, C. A., Fianu, I., & Adelman, K. (2026) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-026-01003-w · Cited by 2 · see citing works
EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery
Wijeratne, H. R. S., Runnebohm, A. M., Barron, M. P., Hampton, A. J., Li, R., Peck Justice, S. A., Lenceski, S. H., Rooney, J. D., Smith-Kinnaman, W. R., Chang, G. S., et al. (2026) · doi:10.64898/2026.01.26.701775 · Cited by 1 · see citing works
SET1/MLL complexes control transcription independently of H3K4me3Preprint
Au, H. Y. A., Szczurek, A., de Krijger, I., Kjelstrup-Osorio, N., Hughes, A. L., Lastuvkova, A., Vermeulen, M., & Klose, R. J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.08.692985 · Cited by 2 · see citing works
Au, A., Southers, A., Kuś, K., Schoemaker, N., Balıkçı, E., Hewes, C., Fournier, M. L., Aydin, E., Hassanein, S. S., Kilchert, C., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.17.694969
The RNA exosome: mechanisms of RNA surveillance, regulation, and disease
Upadhyai, P., Quadri, N., & Chandran, D. (2026) · RNA Biology · doi:10.1080/15476286.2026.2685379
Hierarchical regulation and molecular functions of co-transcriptional splicing
Niu, R., Zhang, A., Rosenfeld, M. G., Fu, X.-D., & Hao, Y. (2026) · 中国科学通报:英文版 · doi:10.1016/j.scib.2026.07.025
Transcription in check at DNA double-strand breaks
Pradel, L., Marnef, A., & Legube, G. (2026) · Trends in Genetics · doi:10.1016/j.tig.2026.06.004
Broad-stroke regulation by DNA sequence-specific transcription factors
Bigelow, Z., & Nechaev, S. (2026) · Biochemistry and Cell Biology · doi:10.1139/bcb-2026-0135
Mechanisms of transcription termination across the coding and noncoding loci of the genome
Song, A., Hu, M., & Chen, F. (2026) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-026-01005-8
RNA polymerase II removal: transcription quality control and gene regulation
Haworth, B., Abyaneh, P., & Vidaković, A. T. (2026) · Transcription · doi:10.1080/21541264.2026.2698182
Transcription elongation by RNA polymerase II: from regulatory complexity to disease
Dioken, D. N., Altendorfer, E., & Mayer, A. (2026) · Trends in Cell Biology · doi:10.1016/j.tcb.2026.08.007
The early RNA decay factor ZC3H18 directs first intron splicing
Rest, M. L., Benbahouche, N. E. H., Kuhn, C. C., Rouvière, J. O., Jakobsen, L., Robert, M.-C., Abrino, J., Rathore, O. S., Zhang, Y., Bugai, A., et al. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.09.009
- Authors
- Estell, C., Łazowski, K., Eaton, J. D., & West, S.
- Affiliations
- University of Exeter (GB)
- Corresponding author
- West, Steven
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2025-11
- Volume
- 85
- Issue
- 21
- Pages
- 3982-3998.e6
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W4415315673
- Cited by
- 16
- References
- 93
- Citations by year
- 2026: 14 · 2025: 2
- FWCI
- 4.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- University of Exeter (218247/Z/19/Z)
- Wellcome Trust (223106/Z/21/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- Integrator complex, RNA polymerase II, transcription termination, RNA polymerase II pausing, U1 snRNP, U1-70K, transcriptional attenuation
- MeSH terms
- Animals, Gene Expression Regulation, Humans, Promoter Regions, Genetic, RNA Polymerase II, Transcription Factors, Transcription, Genetic, Ribonucleoproteins, Small Nuclear, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase 9, Transcription Termination, Genetic
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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