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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    • "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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    • "Western blot analysis revealed that profilin II (a and b) levels were not altered when Smn levels decreased. Furthermore, we examined levels of other SMN binding partners, gemin 2 and gemin 5. Gemins are proteins that form a complex with SMN necessary for snRNP assembly and splicing (Paushkin et al., 2002; Kolb et al., 2007). Gemin 2 is an SMN binding protein that decreases in cultured cells and in mice when SMN is decreased (Wang and Dreyfuss, 2001; Feng et al., 2005; Gabanella et al., 2007). "
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    ABSTRACT: The actin-binding protein plastin 3 (PLS3) has been identified as a modifier of the human motoneuron disease spinal muscular atrophy (SMA). SMA is caused by decreased levels of the survival motor neuron protein (SMN) and in its most severe form causes death in infants and young children. To understand the mechanism of PLS3 in SMA, we have analyzed pls3 RNA and protein in zebrafish smn mutants. We show that Pls3 protein levels are severely decreased in smn(-/-) mutants without a reduction in pls3 mRNA levels. Moreover, we show that both pls3 mRNA and protein stability are unaffected when Smn is reduced. This indicates that SMN affects PLS3 protein production. We had previously shown that, in smn mutants, the presynaptic protein SV2 is decreased at neuromuscular junctions. Transgenically driving human PLS3 in motoneurons rescues the decrease in SV2 expression. To determine whether PLS3 could also rescue function, we performed behavioral analysis on smn mutants and found that they had a significant decrease in spontaneous swimming and turning. Driving PLS3 transgenically in motoneurons rescued both of these defects. These data show that PLS3 protein levels are dependent on SMN and that PLS3 is able to rescue the neuromuscular defects and corresponding movement phenotypes caused by low levels of Smn suggesting that decreased PLS3 contributes to SMA motor phenotypes.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2012; 32(15):5074-84. DOI:10.1523/JNEUROSCI.5808-11.2012 · 6.34 Impact Factor
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