Biochemical defects in minor spliceosome function in the developmental disorder MOPD I

Jafarifar, Faegheh; Dietrich, Rosemary C.; Hiznay, James M.; Padgett, Richard A.

doi:10.1261/rna.045187.114

Cited by 36 publications

(49 citation statements)

References 48 publications

(106 reference statements)

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“…Similarly in dyskeratosis congenita, mutations in either telomerase RNA or dyskerin can lead to reduced telomerase RNA levels (61)(62)(63)(64). Moreover, the developmental disorder microcephalic osteodysplastic primordial dwarfism type I is caused by mutations in the gene coding for U4atac snRNA (65,66), some of which reduce U4atac RNA levels possibly by affecting snRNP assembly (67). An important point is that for all of these disease conditions, we hypothesize that quality control pathways for RNA are reducing the concentrations of the relevant RNAs.…”

Section: Prevention Of Snrna Decapping May Lead To Rescue Of Snrnpmentioning

confidence: 98%

Quality control of assembly-defective U1 snRNAs by decapping and 5′-to-3′ exonucleolytic digestion

Shukla¹,

Parker

2014

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

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The accurate biogenesis of RNA-protein complexes is a key aspect of eukaryotic cells. Defects in Sm protein complex binding to snRNAs are known to reduce levels of snRNAs, suggesting an unknown quality control system for small nuclear ribonucleoprotein (snRNP) assembly. snRNA quality control may also be relevant in spinal muscular atrophy, which is caused by defects in the survival motor neuron (SMN)1 gene, an assembly factor for loading the Sm complex on snRNAs and, when severely reduced, can lead to reduced levels of snRNAs and splicing defects. To determine how assembly-defective snRNAs are degraded, we first demonstrate that yeast U1 Sm-mutant snRNAs are degraded either by Rrp6-or by Dcp2-dependent decapping/ 5′-to-3′ decay. Knockdown of the decapping enzyme DCP2 in mammalian cells also increases the levels of assembly-defective snRNAs and suppresses some splicing defects seen in SMN-deficient cells. These results identify a conserved mechanism of snRNA quality control, and also suggest a general paradigm wherein the phenotype of an "RNP assembly disease" might be suppressed by inhibition of a competing RNA quality control mechanism. E ukaryotic cells contain a growing diversity of functional noncoding ribonucleoprotein (RNP) complexes. The biogenesis of a stable functional RNP complex requires multiple RNAprocessing reactions and assembly with specific RNA-binding proteins. To prevent the formation of aberrant RNPs and to increase the specificity of RNP assembly, eukaryotic cells also contain a number of RNA quality control systems that recognize and degrade aberrant RNAs (1, 2). The full spectrum of RNA quality control mechanisms and their biological impacts remains to be determined.snRNAs may be subject to quality control mechanisms, because mutations in the binding site for the Sm protein complex reduce steady-state snRNA levels, although whether this is directly due to specific RNA decay mechanisms has not been explored (3-5). snRNA quality control may also be triggered by defects in assembly factors. For example, spinal muscular atrophy (SMA) is a neurodegenerative disease caused by low levels of the survival motor neuron (SMN) protein due to mutations in the principal SMN-coding gene SMN1 (6, 7). One role of the SMN complex is to load the Sm protein complex onto the Sm site on snRNAs, which has a consensus sequence of PuAU 4-6 GPu (8-10). Animal models of SMA, as well as in vitro analysis of SMN knockdown cell lines, revealed that a severe decrease in SMN levels leads to a nonuniform reduction in the levels of snRNAs and snRNPs, further leading to perturbations in splicing (11-16). There are contrasting views as to whether the snRNP assembly function of SMN is causative of SMA (17). Transcriptome analysis in some SMN mutant animal models reveals few splicing defects early in disease progression and, at least in Drosophila, raises the possibility that toxicity could be due to SMN deficiency triggering a stress response (18)(19)(20). At the same time, expression of mature snRNPs can rescue motor functio...

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Section: Prevention Of Snrna Decapping May Lead To Rescue Of Snrnpmentioning

confidence: 98%

Quality control of assembly-defective U1 snRNAs by decapping and 5′-to-3′ exonucleolytic digestion

Shukla¹,

Parker

2014

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

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“…human disease phenotypes (Halvorsen et al 2010;Martin et al 2012;Jafarifar et al 2014;Rogler et al 2014;Kutchko et al 2015). However, it is likely that the vast majority of natural and somatic genetic variation is phenotypically benign.…”

Section: Lackey 16mentioning

confidence: 99%

Allele-specific SHAPE-MaP assessment of the effects of somatic variation and protein binding on mRNA structure

Lackey

Coria

Woods

et al. 2018

RNA

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The precise impact of inherited and somatic mutations on messenger RNA (mRNA) structure remains poorly understood. Recent technological advances that leverage next generation sequencing to obtain experimental structure data, such as SHAPE-MaP (Selective 2' Hydroxyl Acylation by Primer Extension and Mutational Profiling), can reveal structural effects of mutations especially when this data is rigorously incorporated in RNA structural modeling. Here we analyze the ability of SHAPE-MaP to detect the relatively subtle structural changes caused by single nucleotide mutations. We find that allele-specific sorting greatly improved the detection ability of SHAPE-MaP. Thus, we used SHAPE-MaP with a novel combination of clone-free robotic mutagenesis and allele-specific sorting to perform a rapid, comprehensive survey of non-coding somatic and inherited riboSNitches in two cancer-associated mRNAs, TPT1 and LCP1. Combined with rigorous thermodynamic modeling of the Boltzmann suboptimal ensemble we identified a subset of somatic and Lackey 2 inherited mutations that change TPT1 and LCP1 RNA structure, with approximately 14% of all variants identified acting as riboSNitches. To confirm that these in vitro structures were biologically relevant, we tested how dependent TPT1 and LCP1 mRNA structures are on their environments. We performed SHAPE-MaP on TPT1 and LCP1 mRNAs in the presence or absence of cellular proteins and found that both TPT1 and LCP1 have similar overall folds in all conditions. RiboSNitches identified within these mRNAs in vitro are likely to exist under biological conditions. Overall, these data reveal a remarkably robust mRNA structural landscape where differences in environmental conditions and most sequence variants do not significantly alter RNA structural ensembles. Finally, predicting riboSNitches in mRNAs from sequence alone remains particularly challenging; these data will provide the community with a benchmark for further algorithmic development.

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“…Microcephalic “osteodysplastic” primordial dwarfism type 1 is caused by mutations in the RNU-4ATAC gene, which impairs its role in splicing a small subset of introns present in approximately 700 human genes that encode proteins with a diverse range of functions, including those involved in DNA replication and repair, transcription, RNA processing, and translation [159]. …”

Section: Defects In Fundamental Cellular Processesmentioning

confidence: 99%

New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth

2017

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Idiopathic short stature is a common condition with a heterogeneous etiology. Advances in genetic methods, including genome sequencing techniques and bioinformatics approaches, have emerged as important tools to identify the genetic defects in families with monogenic short stature. These findings have contributed to the understanding of growth regulation and indicate that growth plate chondrogenesis, and therefore linear growth, is governed by a large number of genes important for different signaling pathways and cellular functions, including genetic defects in hormonal regulation, paracrine signaling, cartilage matrix, and fundamental cellular processes. In addition, mutations in the same gene can cause a wide phenotypic spectrum depending on the severity and mode of inheritance of the mutation.

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Biochemical defects in minor spliceosome function in the developmental disorder MOPD I

Cited by 36 publications

References 48 publications

Quality control of assembly-defective U1 snRNAs by decapping and 5′-to-3′ exonucleolytic digestion

Quality control of assembly-defective U1 snRNAs by decapping and 5′-to-3′ exonucleolytic digestion

Allele-specific SHAPE-MaP assessment of the effects of somatic variation and protein binding on mRNA structure

New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth

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