Molecular Functions of the SMN Complex

Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Journal of Child Neurology (Impact Factor: 1.72). 09/2007; 22(8):990-4. DOI: 10.1177/0883073807305666
Source: PubMed


The SMN complex is essential for the biogenesis of spliceosomal small nuclear ribonucleoproteins and likely functions in the assembly, metabolism, and transport of a diverse number of other ribonucleoproteins. Specifically, the SMN complex assembles 7 Sm proteins into a core structure around a highly conserved sequence of ribonucleic acid (RNA) found in small nuclear RNAs. The complex recognizes specific sequences and structural features of small nuclear RNAs and Sm proteins and assembles small nuclear ribonucleoproteins in a stepwise fashion. In addition to the SMN protein, the SMN complex contains 7 additional proteins known as Gemin2-8, each likely to play a role in ribonucleoprotein biogenesis. This review focuses on the current understanding of the mechanism of the role of the SMN complex in small nuclear ribonucleoprotein assembly and considers the relationship of this function to spinal muscular atrophy.

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    • "Patients with SMA, the most common form of motoneuron disease in children and young adults, have reduced levels of the survival motor neuron (SMN) protein due to deletion or mutations in the SMN1 gene (Lefebvre et al. 1995). SMN interacts with a large number of proteins and is involved in multiple aspects of RNA processing (Kolb et al. 2007; Burghes and Beattie 2009; Li et al. 2014). The most thoroughly described function for SMN is its role in the generation of spliceosomal small nuclear ribonucleoprotein particles (snRNPs) mediating intron excision (Battle et al. 2006). "
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    ABSTRACT: Neuronal function critically depends on coordinated subcellular distribution of mRNAs. Disturbed mRNA processing and axonal transport has been found in spinal muscular atrophy and could be causative for dysfunction and degeneration of motoneurons. Despite the advances made in characterizing the transport mechanisms of several axonal mRNAs, an unbiased approach to identify the axonal repertoire of mRNAs in healthy and degenerating motoneurons has been lacking. Here we used compartmentalized microfluidic chambers to investigate the somatodendritic and axonal mRNA content of cultured motoneurons by microarray analysis. In axons, transcripts related to protein synthesis and energy production were enriched relative to the somatodendritic compartment. Knockdown of Smn, the protein deficient in spinal muscular atrophy, produced a large number of transcript alterations in both compartments. Transcripts related to immune functions, including MHC class I genes, and with roles in RNA splicing were up-regulated in the somatodendritic compartment. On the axonal side, transcripts associated with axon growth and synaptic activity were down-regulated. These alterations provide evidence that subcellular localization of transcripts with axonal functions as well as regulation of specific transcripts with nonautonomous functions is disturbed in Smn-deficient motoneurons, most likely contributing to the pathophysiology of spinal muscular atrophy.
    RNA 09/2014; 20(11). DOI:10.1261/rna.047373.114 · 4.94 Impact Factor
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    • "SMN has high affinity for Gemin2. SMN:Gemin2 interaction has been considered to be one of the critical steps for the assembly of all SMN complexes (57,58). Consistent with the increase in SMN, we found increased levels of Gemin2 in SMA patient cells treated with ASO 283–297. "
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    ABSTRACT: Here, we report a long-distance interaction (LDI) as a critical regulator of alternative splicing of Survival Motor Neuron 2 (SMN2) exon 7, skipping of which is linked to spinal muscular atrophy (SMA), a leading genetic disease of children and infants. We show that this LDI is linked to a unique intra-intronic structure that we term internal stem through LDI-1 (ISTL1). We used site-specific mutations and Selective 2'-Hydroxyl Acylation analyzed by Primer Extension to confirm the formation and functional significance of ISTL1. We demonstrate that the inhibitory effect of ISTL1 is independent of hnRNP A1/A2B1 and PTB1 previously implicated in SMN2 exon 7 splicing. We show that an antisense oligonucleotide-mediated sequestration of the 3' strand of ISTL1 fully corrects SMN2 exon 7 splicing and restores high levels of SMN and Gemin2, a SMN-interacting protein, in SMA patient cells. Our results also reveal that the 3' strand of ISTL1 and upstream sequences constitute an inhibitory region that we term intronic splicing silencer N2 (ISS-N2). This is the first report to demonstrate a critical role of a structure-associated LDI in splicing regulation of an essential gene linked to a genetic disease. Our findings expand the repertoire of potential targets for an antisense oligonucleotide-mediated therapy of SMA.
    Nucleic Acids Research 07/2013; 41(17). DOI:10.1093/nar/gkt609 · 9.11 Impact Factor
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    • "The metazoan SMN complex has been proposed to function in universal eukaryotic processes related to RNA metabolism, including transcription, splicing, ribonucleoprotein (RNP) biogenesis and in neuron-specific functions, like neurite and axon outgrowth, growth cone excitability, mRNA transport and the function of the neuromuscular junction [reviewed in (18–21)]. The most well characterized mechanism of action of the SMN complex is in the assembly of the spliceosomal U-rich small nuclear RNP (UsnRNP) (18,19,22–27). Accordingly, SMN deficiency would alter the stoichiometry of snRNAs that might cause widespread and tissue-specific pre-mRNA splicing defects in SMA mice models (28,29), as well as in the S. pombe model organism carrying a temperature-degron allele of the SMN protein (30). "
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    ABSTRACT: Spinal muscular atrophy is a severe motor neuron disease caused by reduced levels of the ubiquitous Survival of MotoNeurons (SMN) protein. SMN is part of a complex that is essential for spliceosomal UsnRNP biogenesis. Signal recognition particle (SRP) is a ribonucleoprotein particle crucial for co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum. SRP biogenesis is a nucleo-cytoplasmic multistep process in which the protein components, except SRP54, assemble with 7S RNA in the nucleolus. Then, SRP54 is incorporated after export of the pre-particle into the cytoplasm. The assembly factors necessary for SRP biogenesis remain to be identified. Here, we show that 7S RNA binds to purified SMN complexes in vitro and that SMN complexes associate with SRP in cellular extracts. We identified the RNA determinants required. Moreover, we report a specific reduction of 7S RNA levels in the spinal cord of SMN-deficient mice, and in a Schizosaccharomyces pombe strain carrying a temperature-degron allele of SMN. Additionally, microinjected antibodies directed against SMN or Gemin2 interfere with the association of SRP54 with 7S RNA in Xenopus laevis oocytes. Our data show that reduced levels of the SMN protein lead to defect in SRP steady-state level and describe the SMN complex as the first identified cellular factor required for SRP biogenesis.
    Nucleic Acids Research 12/2012; 41(2). DOI:10.1093/nar/gks1224 · 9.11 Impact Factor
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