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Cited by 167RNA Research and SplicingGenomics and Chromatin DynamicsRNA and protein synthesis mechanisms

The Integrator complex cleaves nascent mRNAs to attenuate transcription

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Tatomer, Deirdre C., Elrod, Nathan D., Liang, Dongming, Xiao, Mei-Sheng, Jiang, Jeffrey Z., Jonathan, Michael, Huang, Kai-Lieh, Wagner, Eric J. +2 more·2019·Genes & Development
DOI 10.1101/gad.330167.119PMC PMC6824465

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Abstract

Cellular homeostasis requires transcriptional outputs to be coordinated, and many events post-transcription initiation can dictate the levels and functions of mature transcripts. To systematically identify regulators of inducible gene expression, we performed high-throughput RNAi screening of the Drosophila Metallothionein A (MtnA) promoter. This revealed that the Integrator complex, which has a well-established role in 3′ end processing of small nuclear RNAs (snRNAs), attenuates MtnA transcription during copper stress. Integrator complex subunit 11 (IntS11) endonucleolytically cleaves MtnA transcripts, resulting in premature transcription termination and degradation of the nascent RNAs by the RNA exosome, a complex also identified in the screen. Using RNA-seq, we then identified >400 additional Drosophila protein-coding genes whose expression increases upon Integrator depletion. We focused on a subset of these genes and confirmed that Integrator is bound to their 5′ ends and negatively regulates their transcription via IntS11 endonuclease activity. Many noncatalytic Integrator subunits, which are largely dispensable for snRNA processing, also have regulatory roles at these protein-coding genes, possibly by controlling Integrator recruitment or RNA polymerase II dynamics. Altogether, our results suggest that attenuation via Integrator cleavage limits production of many full-length mRNAs, allowing precise control of transcription outputs.

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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 [87]

    The Results and Discussion report that Integrator cleaves nascent mRNAs to promote premature transcription termination and also processes other RNA classes, including snRNAs. The Discussion says the RNA exosome degrades the short products of mRNA cleavage, but does not establish that processing those other small RNAs requires the exosome. The supplied passages have section labels but no page numbers. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The Integrator complex copurified with the RNA exosome in prior work showing the role of both Integrator and the RNA exosome in premature RNAPII transcription termination.

    “The Integrator complex copurified with the RNA exosome in prior work showing the role of both Integrator and the RNA exosome in premature RNAPII transcription termination87.”

    From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [87]

    The Results (Figure 3C–D; page not available) show RNA exosome components enriched in Integrator subunit purifications, supporting copurification. The Results (Figure 7) and Discussion attribute premature transcription termination to Integrator, but describe the RNA exosome as degrading the short RNAs after cleavage, not as itself causing termination. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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References 60 · Cited by 167

Research works printed but not linked: 59

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Authors
Tatomer, D. C., Elrod, N. D., Liang, D., Xiao, M.-S., Jiang, J. Z., Jonathan, M., Huang, K.-L., Wagner, E. J., Cherry, S., & Wilusz, J. E.
Affiliations
  • University of Pennsylvania (US)
  • The University of Texas Medical Branch at Galveston (US)
Corresponding author
  • Cherry, Sara
  • Wilusz, Jeremy E.
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2019-09-17
Volume
33
Issue
21-22
Pages
1525-1538
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.330167.119
PMC
PMC6824465
OpenAlex
W2973809717
Cited by
167
References
60
Citations by year
2026: 13 · 2025: 15 · 2024: 33 · 2023: 23 · 2022: 23 · 2021: 32 · 2020: 23 · 2019: 3 · 2018: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nc
Locations
  • Genes & Development (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Institutes of Health (R35-GM119735, K99-GM131028, R01-AI122749, R01-AI074951, R01-GM134539)
  • Welch Foundation (H-1889)
  • Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Award
  • Rita Allen Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
Integrator complex, transcriptional attenuation, RNA exosome, copper stress, Drosophila, RNAi screen, RNA polymerase II, gene expression regulation
MeSH terms
Animals, Cell Line, Copper, Drosophila, Endoribonucleases, Gene Expression Regulation, Metallothionein, Promoter Regions, Genetic, Protein Binding, RNA, Messenger, Stress, Physiological, Drosophila Proteins, RNA Cleavage

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