Cited by 16Genomics and Chromatin DynamicsRNA Research and SplicingNuclear Structure and Function

Sequential verification of transcription by Integrator and Restrictor

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Estell, Chris, Łazowski, Krystian, Eaton, Joshua D., West, Steven·2025·Molecular Cell

Abstract

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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Crossref · 10.1016/j.molcel.2025.09.025

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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.”

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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
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

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