An Assembly Chaperone Collaborates with the SMN Complex to Generate Spliceosomal SnRNPs

Chari, Ashwin; Golas, Monika M.; Klingenhäger, Michael; Neuenkirchen, Nils; Sander, Bjoern; Englbrecht, Clemens; Sickmann, Albert; Stark, Holger; Fischer, Utz

doi:10.1016/j.cell.2008.09.020

Cited by 196 publications

(275 citation statements)

References 43 publications

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“…S6D). PRMT5 can symmetrically dimethylate the C-terminal tails of the U snRNP Sm proteins B/B′, D1, D3, and LSm4 in multiple organisms, which may facilitate the recognition of a subset of 5′ splice sites (10,11,(33)(34)(35)(36). Here atprmt5 mutants show a dramatic impairment of the interaction between Prp19C/NTC and AtSmD3b, revealing a previously unidentified function of symmetric arginine dimethylation in the recruitment of Prp19C/ NTC to the spliceosome.…”

Section: Discussionmentioning

confidence: 99%

Recruitment of the NineTeen Complex to the activated spliceosome requires AtPRMT5

Deng

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is involved in a multitude of biological processes in eukaryotes. Symmetric arginine dimethylation mediated by PRMT5 modulates constitutive and alternative pre-mRNA splicing of diverse genes to regulate normal growth and development in multiple species; however, the underlying molecular mechanism remains largely unknown. A genetic screen for suppressors of an Arabidopsis symmetric arginine dimethyltransferase mutant, atprmt5, identified two gain-of-function alleles of pre-mRNA processing factor 8 gene (prp8-8 and prp8-9), the highly conserved core component of the U5 small nuclear ribonucleoprotein (snRNP) and the spliceosome. These two atprmt5 prp8 double mutants showed suppression of the developmental and splicing alterations of atprmt5 mutants. In atprmt5 mutants, the NineTeen complex failed to be assembled into the U5 snRNP to form an activated spliceosome; this phenotype was restored in the atprmt5 prp8-8 double mutants. We also found that loss of symmetric arginine dimethylation of Sm proteins prevents recruitment of the NineTeen complex and initiation of spliceosome activation. Together, our findings demonstrate that symmetric arginine dimethylation has important functions in spliceosome assembly and activation, and uncover a key molecular mechanism for arginine methylation in pre-mRNA splicing that impacts diverse developmental processes.arginine methylation | protein arginine methyltransferase | AtPRMT5 | pre-mRNA splicing | Prp19C/NTC P rotein arginine methyltransferase 5 (PRMT5), a highly conserved type II protein arginine methyltransferase, transfers methyl groups to arginine residues, generating monomethylarginine and symmetric ω-N G , N′ G -dimethylarginine (SDMA) (1-3). In mammals, PRMT5 methylates and interacts with diverse proteins, including histones and other proteins, and has long been implicated in the modulation of a variety of processes, such as transcriptional regulation, RNA metabolism (4), apoptosis (5), signal transduction (6), and germ cell development (7). Both loss-of-function and overexpression of PRMT5 are fatal in mammals (8). AtPRMT5, the Arabidopsis homolog of PRMT5, regulates multiple aspects of plant growth and development, such as flowering time, growth rate, leaf morphology, sensitivity to stress conditions, and circadian rhythm, by modulating transcription, constitutive and alternative precursor mRNA (pre-mRNA) splicing of diverse genes (9-13). AtPRMT5 also mediates the symmetric arginine dimethylation of uridine-rich small nuclear ribonucleoproteins (U snRNPs) AtSmD1, D3, and AtLSm4 proteins, thus linking arginine methylation and splicing (10,11,13). However, the exact mechanism remains elusive.Pre-mRNA splicing occurs in the nucleus, removing introns and ligating exons (14). In eukaryotes, most introns are spliced in a series of reactions catalyzed by the spliceosome, which consists of five subcomplexes of U snRNPs and several non-snRNP factors. Each U snRNP contains distinct splicing...

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Section: Discussionmentioning

confidence: 99%

Recruitment of the NineTeen Complex to the activated spliceosome requires AtPRMT5

Deng

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…SMN deficiency results in widespread splicing defects and, therefore, SMA is a general splicing disease (31). SMN may not be a direct substrate of PRMT5; however, Sm B/B′, D1, and D3 are symmetrically dimethylated by PRMT5, increasing the binding affinity between Sm proteins and SMN-complex to promote U snRNP assembly (44). Although direct evidence between PRMT5 and pre-mRNA splicing is lacking in humans, given the fact that PRMT5 is an evolutionarily conserved protein and symmetric arginine dimethylation of Sm proteins by PRMT5 is required for snRNP assembly (20), it will not be surprising if mutations in human PRMT5 cause widespread splicing defects, which may be because of the multiple functions for PRMT5.…”

Section: Discussionmentioning

confidence: 99%

Arginine methylation mediated by the Arabidopsis homolog of PRMT5 is essential for proper pre-mRNA splicing

Deng

Gu²,

Liu³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

170

182

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Protein arginine methylation, one of the most abundant and important posttranslational modifications, is involved in a multitude of biological processes in eukaryotes, such as transcriptional regulation and RNA processing. Symmetric arginine dimethylation is required for snRNP biogenesis and is assumed to be essential for pre-mRNA splicing; however, except for in vitro evidence, whether it affects splicing in vivo remains elusive. Mutation in an Arabidopsis symmetric arginine dimethyltransferase, AtPRMT5, causes pleiotropic developmental defects, including late flowering, but the underlying molecular mechanism is largely unknown. Here we show that AtPRMT5 methylates a wide spectrum of substrates, including some RNA binding or processing factors and U snRNP AtSmD1, D3, and AtLSm4 proteins, which are involved in RNA metabolism. RNA-seq analyses reveal that AtPRMT5 deficiency causes splicing defects in hundreds of genes involved in multiple biological processes. The splicing defects are identified in transcripts of several RNA processing factors involved in regulating flowering time. In particular, splicing defects at the flowering regulator FLOWERING LOCUS KH DOMAIN (FLK) in atprmt5 mutants reduce its functional transcript and protein levels, resulting in the up-regulation of a flowering repressor FLOWERING LOCUS C (FLC) and consequently late flowering. Taken together, our findings uncover an essential role for arginine methylation in proper premRNA splicing that impacts diverse developmental processes. P RMT5 is a type II protein arginine methyltransferase that catalyzes the formation of monomethylarginine and symmetric ω-N G , N′ G -dimethylarginine (SDMA) (1). PRMT5 is highly conserved among yeast, animals, and higher plants, and is implicated in diverse cellular and biological processes, including transcriptional regulation, RNA metabolism (1, 2), ribosome biogenesis (3), Golgi apparatus structure maintenance (4), and cell cycle regulation (5). In mouse, fly, and worm, PRMT5 orthologs are involved in germ-cell formation, specification, and maintenance (6-10).In mammalian cells, PRMT5 localizes to both the cytoplasm and the nucleus, and methylates multiple histone and nonhistone proteins (1). In the nucleus, PRMT5 usually functions in repressing target genes by methylating histone H4 Arginine 3 (H4R3), H3R8, as well as transcription factors/regulators (5, 11, 12). In the cytoplasm, PRMT5 mainly exists in a 20S methylosome complex, consisting of spliceosomal U snRNP (uridinerich small nuclear riboucleoprotein particles) Sm proteins (including Sm B/B′, D1, D2, D3, E, F, and G), PRMT5, pICln, and WD repeat protein/MEP50 (13-15). In this complex, U1, 2, 4, 5 snRNP Sm proteins Sm B/B′, D1, D3, and U6 snRNP-specific Sm-like protein LSm4 are symmetrically dimethylated by PRMT5 (13,16). Such methylation can increase the binding affinity of these Sm proteins for the downstream recipient, Survival Motor Neuron, the spinal muscular atrophy disease gene product (17,18). Subsequently, the PRMT5-and Survival Motor Neuroncom...

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“…47,48 The Sm proteins are delivered to the SMN complex via the activity of the PRMT5 complex, which methylates C-terminal arginine residues within SmB, SmD1, and SmD3 42,49 and then chaperones delivery of partially assembled Sm subcomplexes. 50,51 Gemin5, a component of the SMN complex, is thought to be the factor responsible for recognition of Sm-class snRNAs. 52 Thus, the SMN complex is thought to provide specificity, to avoid assembly of Sm cores onto non-target RNAs, 43,52 and to accelerate formation of the final product from kinetically trapped intermediates.…”

Section: Smn and Cytoplasmic Snrnp Assemblymentioning

confidence: 99%

“…52 Thus, the SMN complex is thought to provide specificity, to avoid assembly of Sm cores onto non-target RNAs, 43,52 and to accelerate formation of the final product from kinetically trapped intermediates. 51 Assembly of the Sm core not only stabilizes the snRNA by protecting it from nucleases, but also is required for the downstream RNA-processing steps.…”

Section: Smn and Cytoplasmic Snrnp Assemblymentioning

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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An Assembly Chaperone Collaborates with the SMN Complex to Generate Spliceosomal SnRNPs

Cited by 196 publications

References 43 publications

Recruitment of the NineTeen Complex to the activated spliceosome requires AtPRMT5

Recruitment of the NineTeen Complex to the activated spliceosome requires AtPRMT5

Arginine methylation mediated by the Arabidopsis homolog of PRMT5 is essential for proper pre-mRNA splicing

SMN - A chaperone for nuclear RNP social occasions?

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