The Integrator complex cleaves nascent mRNAs to attenuate transcription

Abstract

words)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-throughputRNAi 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 proteincoding 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 non-catalytic 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.

A Two-Layered Targeting Mechanism Underlies Nuclear RNA Sorting by the Human Exosome

“…Our analysis of protein-coding genes argues that this phenomenon is not just restricted to loci producing cryptic transcripts. Moreover, it suggests that TSS-proximal termination events may extend well beyond previously reported examples (Elrod et al, 2019;Iasillo et al, 2017;Kamieniarz-Gdula et al, 2019;Ogami et al, 2017;Tatomer et al, 2020).…”

POINT Technology Illuminates the Processing of Polymerase-Associated Intact Nascent Transcripts

“…Possibly the Integrator complex is responsible for these cleavage sites as a way to regulate PTT. Indeed recent studies have shown that Integrator complex prematurely terminates protein coding genes (Elrod et al, 2019; Tatomer et al, 2019) and also terminates transcription of long noncoding RNA genes (Lai et al, 2015). This suggests that the PTT may be regulated by a combination of CPA and Integrator complexes, similar to termination of lncRNA transcription (Nojima et al, 2018b).…”

ZC3H4 restricts non-coding transcription in human cells

“…Another important role of Integrator is in the promoter-proximal termination of proteincoding gene transcription (Elrod et al, 2019;Lykke-Andersen et al, 2020;Tatomer et al, 2019). Increased full-length transcription of a subset of genes is seen in its absence reflecting escape from this early termination.…”