SMN control of RNP assembly: From post-transcriptional gene regulation to motor neuron disease

Abstract

At the post-transcriptional level, expression of protein-coding genes is controlled by a series of RNA regulatory events including nuclear processing of primary transcripts, transport of mature mRNAs to specific cellular compartments, translation and ultimately, turnover. These processes are orchestrated through the dynamic association of mRNAs with RNA binding proteins and ribonucleoprotein (RNP) complexes. Accurate formation of RNPs in vivo is fundamentally important to cellular development and function, and its impairment often leads to human disease. The survival motor neuron (SMN) protein is key to this biological paradigm: SMN is essential for the biogenesis of various RNPs that function in mRNA processing, and genetic mutations leading to SMN deficiency cause the neurodegenerative disease spinal muscular atrophy. Here we review the expanding role of SMN in the regulation of gene expression through its multiple functions in RNP assembly. We discuss advances in our understanding of SMN activity as a chaperone of RNPs and how disruption of SMN-dependent RNA pathways can cause motor neuron disease.

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

“…The most well-understood role of SMN in the cell is in the assembly of the spliceosomal small nuclear ribonucleoproteins (snRNPs), which are required for the catalysis of intron removal during pre-mRNA splicing (11,12). In vivo, SMN forms a complex composed of Gemins 2-8 and Unr-interacting protein (Unrip) that can be found localized to nuclear bodies called "gems" at steady state (13,14). In its active role in the cytoplasm, the SMN complex assembles a heptameric ring of Sm proteins around each U-rich small nuclear RNA (snRNA) (U1, U2, U4, U4atac, U5, U11, or U12) to form a mature snRNP (15).…”

“…Several recent studies have proposed that defects in mRNA processing can contribute to genome instability (14,28,38). One proposed mechanism for this effect is through the failure to resolve transcriptional R-loops, transient RNA:DNA hybrid structures that form during transcription that displace the nontemplate DNA strand and generate susceptibility to DNA damage if stabilized.…”

SMN - A chaperone for nuclear RNP social occasions?

“…[34][35][36][37] The Sm-class snRNPs consist of uridine-rich snRNAs (e.g. U1, U2, U4, U5), several specific proteins that are unique to each snRNA, and a set of 7 common Sm proteins (B/ B', D1, D2, D3, E, F, and G).…”

“…39 Various reviews focus on this function of SMN. 34,36,37 Once the pre-snRNAs translocate to the cytoplasm, the snRNA nuclear export complex dissociates. 40,41 The SMN complex, which includes SMN and several tightly associated proteins, collectively called Gemins binds newly exported snRNAs.…”

“…More than half of the known SMA patient missense mutations cluster within the YG box. 25,106,107 Furthermore, mutations that completely disrupt SMN's ability to self-oligomerize display severe phenotypes in human SMA patients as well as in animal models. 86,[108][109][110][111][112][113] Despite this strong correlation, the composition and stoichiometry of the various complexes formed by SMN are not well understood.…”