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  • Review Article
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Genomic regulation of transcription and RNA processing by the multitasking Integrator complex

Nature Reviews Molecular Cell Biology volume 24, pages 204–220 (2023)Cite this article

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Abstract

In higher eukaryotes, fine-tuned activation of protein-coding genes and many non-coding RNAs pivots around the regulated activity of RNA polymerase II (Pol II). The Integrator complex is the only Pol II-associated large multiprotein complex that is metazoan specific, and has therefore been understudied for years. Integrator comprises at least 14 subunits, which are grouped into distinct functional modules. The phosphodiesterase activity of the core catalytic module is co-transcriptionally directed against several RNA species, including long non-coding RNAs (lncRNAs), U small nuclear RNAs (U snRNAs), PIWI-interacting RNAs (piRNAs), enhancer RNAs and nascent pre-mRNAs. Processing of non-coding RNAs by Integrator is essential for their biogenesis, and at protein-coding genes, Integrator is a key modulator of Pol II promoter-proximal pausing and transcript elongation. Recent studies have identified an Integrator-specific serine/threonine-protein phosphatase 2A (PP2A) module, which targets Pol II and other components of the basal transcription machinery. In this Review, we discuss how the activity of Integrator regulates transcription, RNA processing, chromatin landscape and DNA repair. We also discuss the diverse roles of Integrator in development and tumorigenesis.

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Fig. 1: Subunits of the mammalian Integrator complex.
Fig. 2: Structural features and assembly of Integrator.
Fig. 3: Integrator terminates transcription of non-coding RNAs.
Fig. 4: Cleavage of nascent pre-mRNA at RNA polymerase II pausing sites.
Fig. 5: Integrator with the phosphatase module inhibits pause release of RNA polymerase II.

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Acknowledgements

Work in the Gardini laboratory is supported by grants from the NIH (R01 HL141326 and CA252223), the American Cancer Society (RSG-18-157-01-DMC) and the G. Harold and Leila Y. Mathers Charitable Foundation (A.G.).

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  1. The Wistar Institute, Philadelphia, PA, USA

    Sarah A. Welsh & Alessandro Gardini

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Both authors researched data for the article and substantially contributed to discussion of the content. A.G. wrote the article and reviewed and/or edited the manuscript before submission.

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Glossary

Carboxy-terminal domain

(CTD). The unstructured and highly repetitive C terminus of the largest subunit of RNA polymerase II. The CTD has roles in transcription regulation and co-transcriptional RNA processing.

Metallo-β-lactamase–β-CASP domain

(MBL–β-CASP). A metallo-β-lactamase fold further extending into a β-CASP globular domain to form an active nuclease site.

U small nuclear RNAs

(U snRNAs). Uridine-rich small nuclear RNAs transcribed by RNA polymerase II that have essential roles in pre-mRNA splicing.

von Willebrand factor type A domain

An alternating sequence of α-helices and β-strands, generally mediating protein–protein interactions.

HEAT repeats

Protein structural motifs composed of tandem repeats of two α-helices linked by a short loop.

OB-fold domain

The oligonucleotide- or oligosaccharide-binding fold is an evolutionarily ancient protein domain capable of binding nucleic acids.

Premature transcription termination

A process that generally occurs when elongating RNA polymerase II is arrested at any point after the transcription start site and before it reaches a canonical termination site, usually resulting in release of unstable transcripts.

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Welsh, S.A., Gardini, A. Genomic regulation of transcription and RNA processing by the multitasking Integrator complex. Nat Rev Mol Cell Biol 24, 204–220 (2023). https://doi.org/10.1038/s41580-022-00534-2

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