The Integrator Complex in Transcription and Development. Issue 11 (November 2020)

• Record Type: Journal Article
• Authors: Mendoza-Figueroa, María Saraí; Tatomer, Deirdre C.; Wilusz, Jeremy E.
• Is Part Of: Trends in biochemical sciences. Volume 45:Issue 11(2020)
• Page Start: 923
• Page End: 934
• Publication Date: 2020-11
• Subjects: enhancer -- immediate-early gene -- IntS11 -- RNA polymerase II -- snRNA -- transcription termination; Biochemistry -- Periodicals; 572
• DOI: 10.1016/j.tibs.2020.07.004
• Languages: English
• ISSNs: 0968-0004

Abstract

Abstract : The Integrator complex is conserved across metazoans and controls the fate of many nascent RNAs transcribed by RNA polymerase II (RNAPII). Among the 14 subunits of Integrator is an RNA endonuclease that is crucial for the biogenesis of small nuclear RNAs and enhancer RNAs. Integrator is further employed to trigger premature transcription termination at many protein-coding genes, thereby attenuating gene expression. Integrator thus helps to shape the transcriptome and ensure that genes can be robustly induced when needed. The molecular functions of Integrator subunits beyond the RNA endonuclease remain poorly understood, but some can act independently of the multisubunit complex. We highlight recent molecular insights into Integrator and propose how misregulation of this complex may lead to developmental defects and disease. Highlights: The multisubunit Integrator complex is conserved across metazoans and harbors the IntS11 RNA endonuclease that can cleave many nascent RNAs transcribed by RNA polymerase II. Cleavage by Integrator is required for the biogenesis of functional small nuclear RNAs and enhancer RNAs, but attenuates the expression of protein-coding mRNAs by triggering premature transcription termination. Integrator activity helps to ensure that immediate-early genes are robustly induced upon sensing a stimulus. The molecular function of most of the noncatalytic Integrator subunits remains unknown, but some can act independently of the multisubunit complex, including at a subset of enhancers and upon activation of the DNA damage response. Depletion or mutation of Integrator subunits often results in developmental defects, including in humans, and can contribute to cancer progression.