Variant snRNPs: New players within the spliceosome system

Abstract

Much evidence is now accumulating that, in addition to their general role in splicing, the components of the core splicing machinery have extensive regulatory potential. In particular, recent evidence has demonstrated that de-regulation of these factors cause the highest extent of alternative splicing changes compared to de-regulation of the classical splicing regulators. This lack of a general inhibition of splicing resonates the differential splicing effects observed in different disease pathologies associated with specific mutations targeting core spliceosomal components. In this review we will summarize what is currently known regarding the involvement of core spliceosomal U-snRNP complexes in perturbed tissue development and human diseases and argue for the existence of a compensatory mechanism enabling cells to cope with drastic perturbations in core splicing components. This system maintains the correct balance of spliceosomal snRNPs through differential expression of variant (v)U-snRNPs.

Keywords: SMA; U1; snRNA; snRNP; spliceosome.

Figure 1.

Human pathologies associated with mutations in core spliceosome components. Schematic depicting the core U-snRNP machineries of both the major and minor spliceosome. Diseases are shown on the right with colour discs and with their abbreviated names. Specific defects targeting shared or distinct components of the spliceosome are colour coded (defects that affect all U-snRNPs (Blue), U4/U5/U6 and U4atac/U5/U6atac snRNPs (Orange), U11/U12 di-snRNP (Green), U2 snRNP (Pink), U5 snRNP (Brown), U6 snRNA (Grey/Yellow), U2 snRNA (Grey/Pink), U4atac snRNA (Grey/Red) and U12 snRNA (Grey/Green)). SMA, spinal muscular atrophy; ALS, amyotrophic lateral sclerosis; HS, hypotrichosis simplex; CCMS, cerebrocostomandibular syndrome; RP, retinitis pigmentosa; MDS, myelodysplastic syndromes; CMML, chronic lymphocytic leukemia; MFDM, mandibulofacial dysostosis with microcephaly; BMKS, Burn-McKeown Syndrome; PN, Poikiloderma with Neutropenia; MOPD1, microcephalic osteodysplastic primordial dwarfism type 1.

Figure 2.

Potential new players in the spliceosome system. Current annotations of the human genome indicate that up to 1,300 variant gene copies exist for each spliceosomal U-snRNA. In the above schematic, different spliceosomal snRNA genes are each denoted by a sphere. The size of each sphere is representative of the number of variant(v) gene copies (141 vU1, 71 vU2, 90 vU4, 37 vU5, 1,300 vU6, 4 vU11, 1 vU12, 18 vU4atac and 42 vU6atac gene copies). The existence of these vU-snRNA genes copies, their regulation and mis-regulation in development and disease, respectively, and their potential involvement in the spliceosome machinery, suggests an additional layer of regulation that has gone unnoticed for decades. We propose that changes within the stoichiometry and composition of U-snRNP repertoires underlie the tissue specific phenotypes associated with different pathologies arising from defects in core spliceosomal components.