snRNA 3' end formation: the dawn of the Integrator complex

Abstract

The ubiquitously expressed uridine-rich snRNAs (small nuclear RNAs) are essential for the removal of introns, proper expression of histone mRNA and biosynthesis of ribosomal RNA. Much is known about their assembly into snRNP (small nuclear ribonucleoprotein) particles and their ultimate function in the expression of other genes; however, in comparison, less is known about the biosynthesis of these critical non-coding RNAs. The sequence elements necessary for 3' end formation of snRNAs have been identified and, intriguingly, the processing of snRNAs is uniquely dependent on the snRNA promoter, indicating that co-transcriptional processing is important. However, the trans-acting RNA-processing factors that mediate snRNA processing remained elusive, hindering overall progress. Recently, the factors involved in this process were biochemically purified, and designated the Integrator complex. Since their initial discovery, Integrator proteins have been implicated not only in the production of snRNA, but also in other cellular processes that may be independent of snRNA biogenesis. In the present study, we discuss snRNA biosynthesis and the roles of Integrator proteins. We compare models of 3' end formation for different classes of RNA polymerase II transcripts and formulate/propose a model of Integrator function in snRNA biogenesis.

Figure 1. Schematic diagram of Integrator protein domains and conservation

Regions identified using Pfam analysis are labelled in black, whereas regions of conservation greater than 80% over a stretch of ten amino acids are labelled in grey (conservation was compared between human, cow, chicken, Drosophila and zebrafish). Abbreviations: ARM, Armadillo-fold repeats; β-CASP, metallo-β-lactamase-associated CPSF Artemis SNM1/PSO2 (*Integrator 9 has these domains inactivated through single amino acid changes); DEAD, RNA helicase DEAD box (*key residues are mutated, probably rendering this domain inactive); DUF, domain of unknown function; HEAT, HEAT repeat units; IntS, Integrator subunit; β-lactamase, metallo-β-lactamase domain (*Integrator 9 has these domains inactivated through single amino acid changes); PHD, plant homeodomain finger; TPR repeats, tetratricopeptide repeats; VWA, von Willebrand factor A fold.

Figure 2. Comparison of the three 3′-end-processing complexes for RNA polymerase II transcripts

The three ‘cleavage factor’ proteins are denoted in light grey for all three systems with the Integrator cleavage factor having one of its unknown subunits labelled with a question mark. The dark-grey proteins represent factors involved in either CTD recognition or cis element binding. CstF, cleavage-stimulation factor; HDE, histone downstream element; RNA Pol II, RNA polymerase II.