Biogenesis of spliceosomal small nuclear ribonucleoproteins

Fischer, Utz; Englbrecht, Clemens; Chari, Ashwin

doi:10.1002/wrna.87

Cited by 122 publications

(125 citation statements)

References 118 publications

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“…Survival motor neuron (SMN) protein functions in the assembly of Sm-class small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome (Fischer et al 2011;Matera and Wang 2014). Loss of SMN causes the neuromuscular disease spinal muscular atrophy (SMA) (Lefebvre et al 1995), but the extent to which SMA is caused by disruptions in snRNP levels is not known.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

Garcia

Wen

Praveen

et al. 2016

RNA

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Survival motor neuron (SMN) functions in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) that catalyze pre-mRNA splicing. Here, we used disruptions in Smn and two additional snRNP biogenesis genes, Phax and Ars2, to classify RNA processing differences as snRNP-dependent or gene-specific in Drosophila. Phax and Smn mutants exhibited comparable reductions in snRNAs, and comparison of their transcriptomes uncovered shared sets of RNA processing changes. In contrast, Ars2 mutants displayed only small decreases in snRNA levels, and RNA processing changes in these mutants were generally distinct from those identified in Phax and Smn animals. Instead, RNA processing changes in Ars2 mutants support the known interaction of Ars2 protein with the cap-binding complex, as splicing changes showed a clear bias toward the first intron. Bypassing disruptions in snRNP biogenesis, direct knockdown of spliceosomal proteins caused similar changes in the splicing of snRNP-dependent events. However, these snRNP-dependent events were largely unaltered in three Smn mutants expressing missense mutations that were originally identified in human spinal muscular atrophy (SMA) patients. Hence, findings here clarify the contributions of Phax, Smn, and Ars2 to snRNP biogenesis in Drosophila, and loss-of-function mutants for these proteins reveal differences that help disentangle cause and effect in SMA model flies.

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Section: Introductionmentioning

confidence: 99%

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

Garcia

Wen

Praveen

et al. 2016

RNA

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“…The survival motor neuron protein (SMN) functions as part of a large multimeric complex in the assembly of Sm-class small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome (Fischer et al 2011). Loss-of-function mutations in human SMN1 cause spinal muscular atrophy (SMA), a genetic disorder characterized by motor neuron degeneration, atrophy of proximal muscles, and symmetrical paralysis .…”

Section: Introductionmentioning

confidence: 99%

Developmental arrest of Drosophila survival motor neuron (Smn) mutants accounts for differences in expression of minor intron-containing genes

Garcia

Meers

et al. 2013

RNA

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Reduced levels of survival motor neuron (SMN) protein lead to a neuromuscular disease called spinal muscular atrophy (SMA). Animal models of SMA recapitulate many aspects of the human disease, including locomotion and viability defects, but have thus far failed to uncover the causative link between a lack of SMN protein and neuromuscular dysfunction. While SMN is known to assemble small nuclear ribonucleoproteins (snRNPs) that catalyze pre-mRNA splicing, it remains unclear whether disruptions in splicing are etiologic for SMA. To investigate this issue, we carried out RNA deep-sequencing (RNA-seq) on agematched Drosophila Smn-null and wild-type larvae. Comparison of genome-wide mRNA expression profiles with publicly available data sets revealed the timing of a developmental arrest in the Smn mutants. Furthermore, genome-wide differences in splicing between wild-type and Smn animals did not correlate with changes in mRNA levels. Specifically, we found that mRNA levels of genes that contain minor introns vary more over developmental time than they do between wild-type and Smn mutants. An analysis of reads mapping to minor-class intron-exon junctions revealed only small changes in the splicing of minor introns in Smn larvae, within the normal fluctuations that occur throughout development. In contrast, Smn mutants displayed a prominent increase in levels of stress-responsive transcripts, indicating a systemic response to the developmental arrest induced by loss of SMN protein. These findings not only provide important mechanistic insight into the developmental arrest displayed by Smn mutants, but also argue against a minor-intron-dependent etiology for SMA.

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“…The U1 snRNP is composed of the U1 snRNA, a ring of seven Sm proteins and a set of specific proteins -U1A, U1C and U1-70K. U1 snRNA is transcribed by RNA polymerase II and exported to the cytoplasm, where the Sm ring is loaded (Fischer et al, 2011). Sm formation is promoted and controlled by the SMN complex, which consists of the survival of motor neuron (SMN) protein, seven Gemin proteins (Gemin2-Gemin8) and unrip (also known as STRAP) (Fischer et al, 1997;Otter et al, 2007;Cauchi, 2010).…”

Section: Introductionmentioning

confidence: 99%

Splicing factor U1-70K interacts with the SMN complex and is required for nuclear Gem integrity

Stejskalová

Staněk

2014

Journal of Cell Science

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The nuclear SMN complex localizes to specific structures called nuclear gems. The loss of gems is a cellular marker for several neurodegenerative diseases. Here, we identify that the U1-snRNPspecific protein U1-70K localizes to nuclear gems, and we show that U1-70K is necessary for gem integrity. Furthermore, we show that the interaction between U1-70K and the SMN complex is RNA independent, and we map the SMN complex binding site to the unstructured N-terminal tail of U1-70K. Consistent with these results, the expression of the U1-70K N-terminal tail rescues gem formation. These findings show that U1-70K is an SMN-complexassociating protein, and they suggest a new function for U1-70K in the formation of nuclear gems.

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Biogenesis of spliceosomal small nuclear ribonucleoproteins

Cited by 122 publications

References 118 publications

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for spinal muscular atrophy

Developmental arrest of Drosophila survival motor neuron (Smn) mutants accounts for differences in expression of minor intron-containing genes

Splicing factor U1-70K interacts with the SMN complex and is required for nuclear Gem integrity

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