Gemin5, a Novel WD Repeat Protein Component of the SMN Complex That Binds Sm Proteins

Gubitz, Amelie K.; Mourelatos, Zissimos P.; Abel, Linda; Rappsilber, Juri; Mann, Matthias; Dreyfuss, Gideon

doi:10.1074/jbc.m109448200

Cited by 137 publications

(125 citation statements)

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“…SMN localizes diffusely throughout the cytoplasm, with intense nuclear signals corresponding to Cajal bodies (Liu and Dreyfuss, 1996;Matera and Frey, 1998). Based on the known protein-protein interactions, organization of the complex centers around SMN, which directly interacts with itself, Gemin2, Gemin3, Gemin5, and Gemin8 Lorson et al, 1998;Charroux et al, 1999;Meister et al, 2000;Baccon et al, 2002;Gubitz et al, 2002;Pellizzoni et al, 2002a;Carissimi et al, 2006a;Battle et al, 2007;Otter et al, 2007). Gemin8 is thought to recruit Gemin6, Gemin7, and unr-interacting protein (UNRIP/STRAP), whereas Gemin3 brings Gemin4 into the complex Baccon et al, 2002;Carissimi et al, 2005Carissimi et al, , 2006b).…”

Section: Introductionmentioning

confidence: 99%

Gemin3Is an Essential Gene Required for Larval Motor Function and Pupation inDrosophila

Shpargel

Praveen

Rajendra

et al. 2009

MBoC

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The assembly of metazoan Sm-class small nuclear ribonucleoproteins (snRNPs) is an elaborate, step-wise process that takes place in multiple subcellular compartments. The initial steps, including formation of the core RNP, are mediated by the survival motor neuron (SMN) protein complex. Loss-of-function mutations in human SMN1 result in a neuromuscular disease called spinal muscular atrophy. The SMN complex is comprised of SMN and a number of tightly associated proteins, collectively called Gemins. In this report, we identify and characterize the fruitfly ortholog of the DEAD box protein, Gemin3. Drosophila Gemin3 (dGem3) colocalizes and interacts with dSMN in vitro and in vivo. RNA interference for dGem3 codepletes dSMN and inhibits efficient Sm core assembly in vitro. Transposon insertion mutations in Gemin3 are larval lethals and also codeplete dSMN. Transgenic overexpression of dGem3 rescues lethality, but overexpression of dSMN does not, indicating that loss of dSMN is not the primary cause of death. Gemin3 mutant larvae exhibit motor defects similar to previously characterized Smn alleles. Remarkably, appreciable numbers of Gemin3 mutants (along with one previously undescribed Smn allele) survive as larvae for several weeks without pupating. Our results demonstrate the conservation of Gemin3 protein function in metazoan snRNP assembly and reveal that loss of either Smn or Gemin3 can contribute to neuromuscular dysfunction.

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Section: Introductionmentioning

confidence: 99%

Gemin3Is an Essential Gene Required for Larval Motor Function and Pupation inDrosophila

Shpargel

Praveen

Rajendra

et al. 2009

MBoC

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“…The core SMN complex consists of SMN and Gemins2-8, and localizes to both the cytoplasm and nucleoplasm (Fischer et al 1997;Charroux et al 1999Charroux et al , 2000Gubitz et al 2002;Pellizzoni et al 2002;Carissimi et al 2006). Recent work by Otter et al (2007) revealed that SMN, Gemin7, and Gemin8 form a central complex to which the other Gemins peripherally associate via multiple interactions.…”

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confidence: 99%

“…The major U snRNAs (U1, U2, U4, and U5) are transcribed in the nucleus and transported to the cytoplasm, where direct interaction with the SMN complex has been demonstrated (Yong et al 2004;Golembe et al 2005). All of the SMN core complex components, with the exception of Gemin2, have been shown to associate with various subsets of so-called Sm proteins (SmB/BЈ, SmD1-3, SmE, SmF, and SmG) that can form a heptameric ring-like structure, known as the Sm core, in the presence of target U snRNAs (Fischer et al 1997;Charroux et al 1999Charroux et al , 2000Baccon et al 2002;Gubitz et al 2002;Pellizzoni et al 2002;Carissimi et al 2006). Sm core formation depends on the presence of a 6-to 8-nucleotide (nt) "Sm site" on the U snRNAs .…”

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confidence: 99%

Inhibition of U snRNP assembly by a virus-encoded proteinase

Almstead¹,

Sarnow²

2007

Genes Dev.

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It has been proposed that defects in the assembly of spliceosomal uridine-rich small nuclear ribonucleoprotein (U snRNP) complexes could account for the death of motor neurons in spinal muscular atrophy (SMA). We discovered that infection of cultured cells with poliovirus results in the specific cleavage of the host factor Gemin3 by a virus-encoded proteinase, 2A pro . Gemin3 is a component of the macromolecular SMN complex that mediates assembly of U snRNP complexes by aiding the heptameric oligomerization of Sm proteins onto U snRNAs. Using in vitro Sm core assembly assays, we found that lowering the intracellular amounts of Gemin3 by either poliovirus infection or small interfering RNA (siRNA)-mediated knockdown of Gemin3 resulted in reduced assembly of U snRNPs. Immunofluorescence analyses revealed a specific redistribution of Sm proteins from the nucleoplasm to the cytoplasmic periphery of the nucleus in poliovirus-infected cells. We propose that defects in U snRNP assembly may be shared features of SMA and poliomyelitis.[Keywords: snRNP assembly; picornaviral proteinases; Gemins] Supplemental material is available at http://www.genesdev.org.

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“…The SMN complex is comprised of several proteins (many still unidentified), including Gemin2-8 and UNRIP (UNR-interacting protein, or STRAP) [Charroux et al, 1999;Charroux et al, 2000;Baccon et al, 2002;Gubitz et al, 2002;Pellizzoni et al, 2002;Carissimi et al, 2006]. The best characterized function of the complex is in the assembly of small nuclear ribonucleoproteins (snRNPs), which are involved in several aspects of RNA metabolism [see Workman et al, 2012 for a review].…”

Section: Smn: How Many Functions Can a Single Protein Possess?mentioning

confidence: 99%

“…However, because SMN is part of a very large multimeric complex, it is possible that SMND7 is stabilized in vivo due to its association with other proteins in the complex [Burghes and Beattie, 2009]. In favor of this hypothesis is the observation that expression of the SMND7 isoform in a Smn À/À ; SMN2 þ/þ background dramatically improves the survival of a severe mouse model of the disease [Le et al, 2005].The SMN complex is comprised of several proteins (many still unidentified), including Gemin2-8 and UNRIP (UNR-interacting protein, or STRAP) [Charroux et al, 1999;Charroux et al, 2000;Baccon et al, 2002;Gubitz et al, 2002;Pellizzoni et al, 2002;Carissimi et al, 2006]. The best characterized function of the complex is in the assembly of small nuclear ribonucleoproteins (snRNPs), which are involved in several aspects of RNA metabolism [see Workman et al, 2012 for a review].…”

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confidence: 99%

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

Tiziano

Melki

Simard

2013

American J of Med Genetics Pt A

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Spinal muscular atrophy (SMA) is an autosomal recessive, lower motor neuron disease. Clinical heterogeneity is pervasive: three infantile (type I-III) and one adult-onset (type IV) forms are recognized. Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA. Most forms of SMA are caused by mutations of the survival motor neuron (SMN1) gene. A second gene that is 99% identical to SMN1 (SMN2) is located in the same region. The only functionally relevant difference between the two genes identified to date is a C ! T transition in exon 7 of SMN2, which determines an alternative spliced isoform that predominantly excludes exon 7. Thus, SMN2 genes do not produce sufficient full length SMN protein to prevent the onset of the disease. Since the identification of the causative mutation, biomedical research of SMA has progressed by leaps and bounds: from clues on the function of SMN protein, to the development of different models of the disease, to the identification of potential treatments, some of which are currently in human trials. The aim of this review is to elucidate the current state of knowledge, emphasizing how close we are to the solution of the puzzle that is SMA, and, more importantly, to highlight the missing pieces of this puzzle. Filling in these gaps in our knowledge will likely accelerate the development and delivery of efficient treatments for SMA patients and be a prerequisite towards achieving our final goal, the cure of SMA. Ó 2013 Wiley Periodicals, Inc. Key words: spinal muscular atrophy; SMN INTRODUCTIONSpinal muscular atrophy (SMA) is a lower motor neuron disease that predominantly affects spinal cord anterior horn cells and brain stem nuclei [Dubowitz, 1995; reviewed in Hamilton and Gillingwater, 2013]. Alpha-motor neuron cell degeneration results in progressive, symmetrical skeletal muscle atrophy of limbs and trunk, spreading proximal to distal [Crawford and Pardo, 1996]. Clinical heterogeneity is pervasive: based on the age of onset and on the maximum motor achievement of patients, three infantile (type I-III) and one adult-onset (type IV) forms are commonly recognized. Classification criteria are summarized in Table I. However, this rigid classification does not accurately depict the range of SMA clinical phenotypes, which display a more continuous spectrum, ranging from prenatal onset to almost asymptomatic patients. SMA is a common autosomal recessive disorder (incidence is $1 in 6,000 in most ethnicities). Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA [Crawford and Pardo, 1996;Prior, 2010].Most forms of SMA are caused by mutations in the survival motor neuron (SMN) gene, which was isolated in 1995 in chromosome 5q13 harboring a segmental duplication [Lefebvre et al., 1995]. Mutations in SMN1 are responsible for the four forms of SMA [Wirth, 2000;Alías et al., 2009]. A second gene that is 99% identical to SMN1, the SMN2 gene, is located in the same region [Le...

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Gemin5, a Novel WD Repeat Protein Component of the SMN Complex That Binds Sm Proteins

Cited by 137 publications

References 48 publications

Gemin3Is an Essential Gene Required for Larval Motor Function and Pupation inDrosophila

Gemin3Is an Essential Gene Required for Larval Motor Function and Pupation inDrosophila

Inhibition of U snRNP assembly by a virus-encoded proteinase

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

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