The Spinal Muscular Atrophy Disease Gene Product, Smn

Carvalho, Tereza Cristina de; Almeida, Fátima; Calapez, Alexandre; Lafarga, Miguel; Berciano, Marı́a T.; Carmo‐Fonseca, Maria

doi:10.1083/jcb.147.4.715

Cited by 203 publications

(62 citation statements)

References 78 publications

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“…2A) likely occurs in nucleoli and/or Cajal bodies. Fibrillarin is found primarily in nucleoli where snoRNPs function and also in Cajal bodies where it has been proposed that snoRNP (and snRNP) assembly and biogenesis occur (11,(47)(48)(49)(50)(51)(52)(53)(54). In adult tissues, SMN is also present in Cajal bodies (54 -58) (although in most fetal tissues and some cultured cell types SMN is found in distinct nuclear structures termed gems (34,58,59)).…”

Section: Discussionmentioning

confidence: 99%

Direct Interaction of the Spinal Muscular Atrophy Disease Protein SMN with the Small Nucleolar RNA-associated Protein Fibrillarin

Jones¹,

Gorzynski²,

Hales³

et al. 2001

Journal of Biological Chemistry

151

133

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Fibrillarin is one of four proteins known to interact selectively with all Box C/D family small nucleolar (sno) 1 RNAs (1-6). In eukaryotes, large numbers of snoRNAs direct cleavages and specific nucleotide modifications of pre-rRNA that are required for ribosome biogenesis (7-11). Most Box C/D family snoRNAs guide the site-specific 2Ј-O-methylation of rRNA (12,13). snoRNAs function as RNA-protein complexes known as small nucleolar ribonucleoprotein particles (snoRNPs) (11,14).Fibrillarin has sequence and structural homology to known methyltransferases (15, 16). This observation, coupled with functional studies in yeast (17), has led to the hypothesis that fibrillarin is the catalytic factor in Box C/D snoRNA-directed 2Ј-O-methylation of ribosomal RNA.The survival motor neuron (SMN) protein is linked with one of the most common inheritable causes of childhood mortality, spinal muscular atrophy (SMA) (18 -21). The SMN1 gene is deleted or mutated in patients with SMA (22) resulting in loss of spinal motor neurons accompanied by progressive muscular atrophy.SMN has been implicated in an array of cellular pathways. Antibody inhibition experiments have demonstrated that SMN is required for the biogenesis of spliceosomal small nuclear RNPs (snRNPs) (23, 24), and studies using in vitro splicing systems and yeast mutants have demonstrated a key role for SMN in pre-mRNA splicing (25-27). SMN has also been implicated in regulation of gene expression at the transcriptional level (28,29), in the assembly of the polymerase II transcription machinery (30), and as a neuron-specific anti-apoptotic factor (31-33).To learn more about snoRNP biogenesis and structure, we performed a yeast two-hybrid screen for proteins that interact with Xenopus fibrillarin. We identified the survival motor neuron (SMN) gene multiple times in screens of both Xenopus and human cDNA libraries. Fibrillarin had been detected previously in a two-hybrid screen using SMN (34). We have now demonstrated an in vivo interaction between SMN and fibrillarin, and we show that the two proteins interact directly in vitro. We have mapped the domains of each protein responsible for the interaction, and we found that SMN interacts with fibrillarin and the SmB snRNP protein via the same domain. Our findings suggest a function for SMN in the biogenesis and/or function of snoRNPs (similar to its established role with snRNPs (23-26, 35, 36)).EXPERIMENTAL PROCEDURES

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Section: Discussionmentioning

confidence: 99%

Direct Interaction of the Spinal Muscular Atrophy Disease Protein SMN with the Small Nucleolar RNA-associated Protein Fibrillarin

Jones¹,

Gorzynski²,

Hales³

et al. 2001

Journal of Biological Chemistry

151

133

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“…These are structures previously implicated in the biogenesis and recycling of snRNPs ( (27,29,32,68). However, apart from their colocalization in Cajal bodies, the SPF30 and SMN proteins have distinct cellular distributions.…”

Section: Discussionmentioning

confidence: 99%

SPF30 Is an Essential Human Splicing Factor Required for Assembly of the U4/U5/U6 Tri-small Nuclear Ribonucleoprotein into the Spliceosome

Rappsilber¹,

Ajuh²,

Lamond³

et al. 2001

Journal of Biological Chemistry

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Spliceosome assembly involves the sequential recruitment of small nuclear ribonucleoproteins (snRNPs) onto a pre-mRNA substrate. Although several non-snRNP proteins function during the binding of U1 and U2 snRNPs, little is known about the subsequent binding of the U4/U5/U6 tri-snRNP. A recent proteomic analysis of the human spliceosome identified SPF30 (Neubauer, G., King, A., Rappsilber, J., Calvio, C., Watson, M., Ajuh, P., Sleeman, J., Lamond, A., and Mann, M. (1998) Nat. Genet. 20, 46 -50), a homolog of the survival of motor neurons (SMN) protein, as a spliceosome factor. We show here that SPF30 is a nuclear protein that associates with both U4/U5/U6 and U2 snRNP components. In the absence of SPF30, the preformed tri-snRNP fails to assemble into the spliceosome. Mass spectrometric analysis shows that a recombinant glutathione S-transferase-SPF30 fusion protein associates with complexes containing core Sm and U4/U5/U6 tri-snRNP proteins when added to HeLa nuclear extract, most strongly to U4/U6 -90. The data indicate that SPF30 is an essential human splicing factor that may act to dock the U4/U5/U6 tri-snRNP to the A complex during spliceosome assembly or, alternatively, may act as a late assembly factor in both the tri-snRNP and the A-complex.The splicing of nuclear mRNA precursors, pre-mRNAs, is an essential step for the expression of all intron-containing eukaryotic genes. Splicing takes place in the nucleus, in most cases directly on nascent gene transcripts. The splicing mechanism removes introns in a two-step mechanism involving sequential transesterification reactions and is catalyzed by a dedicated machinery termed the spliceosome (reviewed by Ref.2). The spliceosome complex is composed of small nuclear ribonucleoprotein (snRNP) 1 subunits; specifically, the U1, U2, U4, U5, and U6 snRNPs. The U4/U5/U6 snRNPs preassemble into a tri-snRNP subunit before joining the spliceosome. In addition to the snRNPs, a group of additional protein splicing factors is also present in spliceosomes.In vitro studies in both mammalian and yeast systems have shown that spliceosomes assemble on pre-mRNAs in a stepwise pathway involving the sequential binding of the U1, U2, and U4/U5/U6 snRNP subunits. Thus, assembly of the active spliceosome is preceded by the formation of partial complexes corresponding to assembly intermediates (3-5). The U1 snRNP binds to the 5Ј splice site of the nuclear pre-mRNA (6) assisted by non-snRNP proteins like ASF/SF2 (7), whereas a protein complex termed U2AF (U2 snRNP auxiliary factor) associates with the 3Ј splice site (8). The two splice sites are thought to be bridged by members of the SR protein family, proteins with a sequence stretch rich in alternating serine and arginine residues (9, 10). This assembly intermediate is called mammalian E complex (or yeast commitment complex), and it subsequently recruits U2 snRNP to form the A complex (3, 11-13). A number of non-snRNP protein factors are also required for formation of these intermediate complexes. For example, protein factors in the E...

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“…67,139,140 Understanding the function of the SMN complex within the Cajal body has been a much slower process. As discussed in the preceding paragraphs, the nuclear fraction of SMN may well participate in both early and late events in the biogenesis of spliceosomal snRNPs.…”

Section: Discussionmentioning

confidence: 99%

SMN - A chaperone for nuclear RNP social occasions?

2016

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Survival Motor Neuron (SMN) protein localizes to both the nucleus and the cytoplasm. Cytoplasmic SMN is diffusely localized in large oligomeric complexes with core member proteins, called Gemins. Biochemical and cell biological studies have demonstrated that the SMN complex is required for the cytoplasmic assembly and nuclear transport of Sm-class ribonucleoproteins (RNPs). Nuclear SMN accumulates with spliceosomal small nuclear (sn)RNPs in Cajal bodies, sub-domains involved in multiple facets of snRNP maturation. Thus, the SMN complex forms stable associations with both nuclear and cytoplasmic snRNPs, and plays a critical role in their biogenesis. In this review, we focus on potential functions of the nuclear SMN complex, with particular emphasis on its role within the Cajal body.

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The Spinal Muscular Atrophy Disease Gene Product, Smn

Cited by 203 publications

References 78 publications

Direct Interaction of the Spinal Muscular Atrophy Disease Protein SMN with the Small Nucleolar RNA-associated Protein Fibrillarin

Direct Interaction of the Spinal Muscular Atrophy Disease Protein SMN with the Small Nucleolar RNA-associated Protein Fibrillarin

SPF30 Is an Essential Human Splicing Factor Required for Assembly of the U4/U5/U6 Tri-small Nuclear Ribonucleoprotein into the Spliceosome

SMN - A chaperone for nuclear RNP social occasions?

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