PT  - JOURNAL ARTICLE
AU  - Deirdre C. Tatomer
AU  - Nathan D. Elrod
AU  - Dongming Liang
AU  - Mei-Sheng Xiao
AU  - Jeffrey Z. Jiang
AU  - Michael Jonathan
AU  - Kai-Lieh Huang
AU  - Eric J. Wagner
AU  - Sara Cherry
AU  - Jeremy E. Wilusz
TI  - The Integrator complex cleaves nascent mRNAs to attenuate transcription
AID  - 10.1101/748319
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 748319
4099  - http://biorxiv.org/content/early/2019/08/28/748319.short
4100  - http://biorxiv.org/content/early/2019/08/28/748319.full
AB  - 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 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.