At the Intersection of Major and Minor Spliceosomes: Crosstalk Mechanisms and Their Impact on Gene Expression

Abstract

Many eukaryotic species contain two separate molecular machineries for removing non-coding intron sequences from pre-mRNA molecules. The majority of introns (more than 99.5% in humans) are recognized and excised by the major spliceosome, which utilizes relatively poorly conserved sequence elements at the 5' and 3' ends of the intron that are used for intron recognition and in subsequent catalysis. In contrast, the minor spliceosome targets a rare group of introns (approximately 0.5% in humans) with highly conserved sequences at the 5' and 3' ends of the intron. Minor introns coexist in the same genes with major introns and while the two intron types are spliced by separate spliceosomes, the two splicing machineries can interact with one another to shape mRNA processing events in genes containing minor introns. Here, we review known cooperative and competitive interactions between the two spliceosomes and discuss the mechanistic basis of the spliceosome crosstalk, its regulatory significance, and impact on spliceosome diseases.

Keywords: RNA processing; cryptic splicing; exon definition; mRNA splicing; major spliceosome; minor spliceosome; minor spliceosome disease.

FIGURE 1

(A) Consensus splice site sequences of minor and major introns. Minor or U12-type introns can additionally be grouped into AT-AC and GT-AG subtypes based on the first and last di-nucleotides. (B) Schematic of exon definition interactions taking place in a typical minor intron containing gene flanked by U2-type introns. Selected snRNA and protein components are indicated. Exons are depicted as solid boxes and introns as lines. Regulatory elements within exons are depicted as blue bars. Figure in panel (B) was modified from Turunen et al. (2013a). Created by BioRender.com.

FIGURE 2

Cooperation between minor and major spliceosomes. Feedback regulation in the minor RNPC3(65K) gene is mediated by protein-protein interactions between the U11/U12 di-snRNP bound to the USSE and upstream U2AF1/2 to enhance recognition of an upstream 3′ss. Cp factors denote cleavage and polyadenylation factors. This leads to formation of either productive mRNA translated in the cytoplasm, or unproductive mRNA that is retained in the nucleus. Modified from Verbeeren et al. (2017). Created by BioRender.com.

FIGURE 3

Competition between minor and major spliceosomes. Examples of known genes utilizing adjacent U12-and U2-type introns in regulating gene expression. The U2-type splicing is indicated with black lines and U12-type splicing with orange lines. Alternative exon sequences are indicated with light gray shading. With SRSF10 an alternative poly-A site (pA) downstream of exon 3 is indicated. In the same panel, the rare U12-type splice site usage downstream of the exon 3 is indicated by dotted orange line.

FIGURE 4

Schematics showing examples of cryptic splice site activation in defective minor intron splicing. The U2-type splicing is indicated with black lines and U12-type splicing with orange lines. Constitutive splicing is indicated with solid lines and cryptic splicing with dotted lines. Alternative exon sequences are indicated with light gray shading. With LKB1 the additional cryptic splice sites are indicated by dotted vertical lines.