Spliceosomal small nuclear ribonucleoprotein biogenesis defects and motor neuron selectivity in spinal muscular atrophy

Abstract

The SMN protein is essential and participates in the assembly of macromolecular complexes of RNA and protein in all cells. The best-characterized function of SMN is as an assembler of spliceosomal small nuclear ribonucleoproteins (snRNPs). SMN performs this function as part of a complex with several other proteins called Gemins. snRNPs are assembled in the cytoplasm in a stepwise manner and then are imported to the nucleus where they participate globally in the splicing of pre-mRNA. Mutations in the SMN1 gene result in the motor neuron disease, spinal muscular atrophy (SMA). Most of these mutations result in a reduction in the expression levels of the SMN protein, which, in turn, results in a reduction in snRNP assembly capacity. This review highlights current studies that have investigated the mechanism of SMN-dependent snRNP assembly, as well as the downstream effects on pre-mRNA splicing that result from a decrease in SMN. This article is part of a Special Issue entitled "RNA-Binding Proteins".

Fig. 1

The role of SMN in snRNP biogenesis. Following transcription, snRNAs are exported to the cytoplasm where they are bound by Gemin5 and delivered to SMN for Sm core assembly. Sm proteins are methylated in the cytoplasm by PRMT5 and then transferred to pICln, which delivers them to the SMN complex. The SMN complex binds Sm proteins through at least 2 binding modes: 1) SMN binds to sDMA tails on Sm B, D1 and D3, and 2) Gemin2 recognizes the Sm-fold of the Sm D1/D2/E/F/G pentamer. Several SMA patient mutations disrupt these binding activities. SMN forms oligomers and is depicted here as a tetramer for simplicity. The SMN complex then assembles the Sm proteins into a heptameric ring on the snRNA. Assembled snRNPs are then imported into the nucleus for final maturation and function in pre-mRNA splicing.