The Integrator complex terminates promoter-proximal transcription at protein-coding genes

Abstract

SUMMARYThe 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 25-60 nucleotide-long nascent RNA for many minutes while awaiting signals for release into the gene body. However, a number 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, 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.HighlightsThe Integrator complex inhibits transcription elongation at ∼15% of mRNA genesIntegrator targets promoter-proximally paused Pol II for terminationThe RNA endonuclease of Integrator subunit 11 is critical for gene attenuationIntegrator-repressed genes are enriched in signaling and growth-responsive pathways