The Integrator Complex Attenuates Promoter-Proximal Transcription at Protein-Coding Genes

Nathan D. Elrod, Telmo Henriques, Kai Lieh Huang, Deirdre C. Tatomer, Jeremy E. Wilusz, Eric J. Wagner, Karen Adelman

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

The transition of RNA polymerase II (Pol II) from initiation to productive elongation is a central, regulated step in metazoan gene expression. At many genes, Pol II pauses stably in early elongation, remaining engaged with the 25- to 60-nt-long nascent RNA for many minutes while awaiting signals for release into the gene body. However, 15%–20% of genes display highly unstable promoter Pol II, suggesting that paused polymerase might dissociate from template DNA at these promoters and release a short, non-productive mRNA. Here, we report that paused Pol II can be actively destabilized by the Integrator complex. Specifically, we present evidence that Integrator utilizes its RNA endonuclease activity to cleave nascent RNA and drive termination of paused Pol II. These findings uncover a previously unappreciated mechanism of metazoan gene repression, akin to bacterial transcription attenuation, wherein promoter-proximal Pol II is prevented from entering productive elongation through factor-regulated termination. Here, Elrod et al. demonstrate that the Integrator complex associates with paused RNA polymerase II at promoters and enhancers to terminate RNA synthesis. This attenuation mechanism potently represses expression of both stress- and growth-responsive genes in Drosophila and mammalian cells.

Original languageEnglish (US)
Pages (from-to)738-752.e7
JournalMolecular cell
Volume76
Issue number5
DOIs
StatePublished - Dec 5 2019

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Keywords

  • enhancer RNA
  • histone methylation
  • Integrator complex
  • polymerase pausing
  • transcription regulation
  • transcription termination

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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