Cited by 184Genomics and Chromatin DynamicsRNA Research and SplicingChromatin Remodeling and Cancer

Integrator recruits protein phosphatase 2A to prevent pause release and facilitate transcription termination

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Huang, Kai-Lieh, Jee, David, Stein, Chad B., Elrod, Nathan D., Henriques, Telmo, Mascibroda, Lauren G., Baillat, David, Russell, William K. +2 more·2020·Molecular Cell

Abstract

Efficient release of promoter-proximally paused RNA Pol II into productive elongation is essential for gene expression. Recently, we reported that the Integrator complex can bind paused RNA Pol II and drive premature transcription termination, potently attenuating the activity of target genes. Premature termination requires RNA cleavage by the endonuclease subunit of Integrator, but the roles of other Integrator subunits in gene regulation have yet to be elucidated. Here we report that Integrator subunit 8 (IntS8) is critical for transcription repression and required for association with protein phosphatase 2A (PP2A). We find that Integrator-bound PP2A dephosphorylates the RNA Pol II C-terminal domain and Spt5, preventing the transition to productive elongation. Thus, blocking PP2A association with Integrator stimulates pause release and gene activity. These results reveal a second catalytic function associated with Integrator-mediated transcription termination and indicate that control of productive elongation involves active competition between transcriptional kinases and phosphatases.

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Crossref · 10.1016/j.molcel.2020.08.016

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  • Blots were probed using Drosophila-specific antibodies raised against recombinant GST fusion proteins expressed in E. coli.

    “Blots were probed as previously described using Drosophila-specific antibodies raised against recombinant GST fusion proteins expressed in E. coli (Huang et al., 2020).”

    From Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq (2022) · cites this paper as Huang et al., 2020

    The STAR METHODS sections on antibody generation and Western blotting say that custom antibodies against Drosophila proteins were raised using recombinant proteins expressed in E. coli and that blots were probed with custom and commercial antibodies. Our copy does not identify those recombinant proteins as GST fusion proteins, and not all antibodies used for blots were raised this way. (LLM, conf=0.88)

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Authors
Huang, K.-L., Jee, D., Stein, C. B., Elrod, N. D., Henriques, T., Mascibroda, L. G., Baillat, D., Russell, W. K., Adelman, K., & Wagner, E. J.
Affiliations
  • The University of Texas Medical Branch at Galveston (US)
  • Harvard University (US)
Corresponding author
  • Adelman, Karen
  • Wagner, Eric J.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2020-10
Volume
80
Issue
2
Pages
345-358.e9
ISSN
1097-2765 (ISSN-L)
OpenAlex
W3089290065
Cited by
184
References
83
Citations by year
2026: 27 · 2025: 26 · 2024: 40 · 2023: 36 · 2022: 27 · 2021: 26 · 2020: 2
FWCI
7.37
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Welch Foundation
  • National Institute of Environmental Health Sciences
  • Cancer Prevention and Research Institute of Texas
  • National Institute of General Medical Sciences
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 › Chromatin Remodeling and Cancer
Keywords
Integrator complex, protein phosphatase 2A, RNA polymerase II, transcription termination, promoter-proximal pausing, pause release, RNA cleavage, Spt5, transcription elongation, transcriptional repression
MeSH terms
Amino Acid Sequence, Animals, Drosophila melanogaster, Gene Expression Regulation, Humans, Phosphorylation, Promoter Regions, Genetic, RNA Polymerase II, Substrate Specificity, Transcription Factors, Signal Transduction, Conserved Sequence, Amino Acid Motifs, Protein Subunits, Drosophila Proteins, Protein Phosphatase 2, Genetic Loci, Transcription Termination, Genetic

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