Defective control of pre–messenger RNA splicing in human disease

Chabot, Benoît; Shkreta, Lulzim

doi:10.1083/jcb.201510032

Cited by 190 publications

(165 citation statements)

References 175 publications

(223 reference statements)

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“…The maturation of the snRNAs in the cytoplasm consists of a series of tightly regulated, strictly ordered molecular events highlighted by the assembly of the Sm ring and hypermethylation of the m 7 G cap (Matera and Wang 2014). It has been reported that the survival of motor neuron (SMN) complex facilitates the assembly of the Sm ring complex on the Sm site [A(U) 4-6 G] of pre-snRNAs and safeguards against aberrant snRNP biogenesis and splicing-associated human syndromes, such as spinal muscular atrophy and cancers Golembe et al 2005;Matera and Wang 2014;Chabot and Shkreta 2016).…”

mentioning

confidence: 99%

Structural insights into Gemin5-guided selection of pre-snRNAs for snRNP assembly

Ishikawa

Izumikawa

et al. 2016

Genes Dev.

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In cytoplasm, the survival of motor neuron (SMN) complex delivers pre-small nuclear RNAs (pre-snRNAs) to the heptameric Sm ring for the assembly of the ring complex on pre-snRNAs at the conserved Sm site [A(U) 4-6 G]. Gemin5, a WD40 protein component of the SMN complex, is responsible for recognizing pre-snRNAs. In addition, Gemin5 has been reported to specifically bind to the m 7 G cap. In this study, we show that the WD40 domain of Gemin5 is both necessary and sufficient for binding the Sm site of pre-snRNAs by isothermal titration calorimetry (ITC) and mutagenesis assays. We further determined the crystal structures of the WD40 domain of Gemin5 in complex with the Sm site or m 7 G cap of pre-snRNA, which reveal that the WD40 domain of Gemin5 recognizes the Sm site and m 7 G cap of pre-snRNAs via two distinct binding sites by respective base-specific interactions. In addition, we also uncovered a novel role of Gemin5 in escorting the truncated forms of U1 pre-snRNAs for proper disposal. Overall, the elucidated Gemin5 structures will contribute to a better understanding of Gemin5 in small nuclear ribonucleic protein (snRNP) biogenesis as well as, potentially, other cellular activities.

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mentioning

confidence: 99%

Structural insights into Gemin5-guided selection of pre-snRNAs for snRNP assembly

Ishikawa

Izumikawa

et al. 2016

Genes Dev.

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“…An important field of investigation is how dysregulation of splicing can be involved in cancerogenesis [258, 259]. Splicing defects in cancer cells can result from base-pair substitutions in splice sites or in splicing regulatory sequences.…”

Section: Formation and Export Of Mrnps Linked To Diseasementioning

confidence: 99%

Integration of mRNP formation and export

Björk

Wieslander

2017

Cell. Mol. Life Sci.

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Expression of protein-coding genes in eukaryotes relies on the coordinated action of many sophisticated molecular machineries. Transcription produces precursor mRNAs (pre-mRNAs) and the active gene provides an environment in which the pre-mRNAs are processed, folded, and assembled into RNA–protein (RNP) complexes. The dynamic pre-mRNPs incorporate the growing transcript, proteins, and the processing machineries, as well as the specific protein marks left after processing that are essential for export and the cytoplasmic fate of the mRNPs. After release from the gene, the mRNPs move by diffusion within the interchromatin compartment, making up pools of mRNPs. Here, splicing and polyadenylation can be completed and the mRNPs recruit the major export receptor NXF1. Export competent mRNPs interact with the nuclear pore complex, leading to export, concomitant with compositional and conformational changes of the mRNPs. We summarize the integrated nuclear processes involved in the formation and export of mRNPs.

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“…As more than 90% of human genetic variation maps outside protein-coding regions, at inter- or intragenic sequences, and >40% maps within introns (Maurano et al, 2012), it is attractive to hypothesize that mutations at RS-sites may contribute to disease manifestation. Splicing defects are now well-established contributors in various diseases (Chabot and Shkreta, 2016), and RS, yet another layer of splicing regulation, remains unexplored. In fact, when we intersected a list of high-confidence RS-sites from human brain (Sibley et al, 2015) or endothelial cells (Kelly et al, 2015) to an ensemble of all putatively disease-causative human SNPs, they overlapped (within the 40 preceding the RS-junction) those associated with neurological (e.g., Parkinson's disease, cognitive performance) or circulatory disorders/traits (e.g., retinal vascular caliper, blood pressure), respectively, more than what was expected by chance (A. Papantonis; unpublished data).…”

Section: Regulatory and Disease Implications Of Recursive Splicingmentioning

confidence: 99%

Cutting a Long Intron Short: Recursive Splicing and Its Implications

2016

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Over time eukaryotic genomes have evolved to host genes carrying multiple exons separated by increasingly larger intronic, mostly non-protein-coding, sequences. Initially, little attention was paid to these intronic sequences, as they were considered not to contain regulatory information. However, advances in molecular biology, sequencing, and computational tools uncovered that numerous segments within these genomic elements do contribute to the regulation of gene expression. Introns are differentially removed in a cell type-specific manner to produce a range of alternatively-spliced transcripts, and many span tens to hundreds of kilobases. Recent work in human and fruitfly tissues revealed that long introns are extensively processed cotranscriptionally and in a stepwise manner, before their two flanking exons are spliced together. This process, called “recursive splicing,” often involves non-canonical splicing elements positioned deep within introns, and different mechanisms for its deployment have been proposed. Still, the very existence and widespread nature of recursive splicing offers a new regulatory layer in the transcript maturation pathway, which may also have implications in human disease.

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Defective control of pre–messenger RNA splicing in human disease

Cited by 190 publications

References 175 publications

Structural insights into Gemin5-guided selection of pre-snRNAs for snRNP assembly

Structural insights into Gemin5-guided selection of pre-snRNAs for snRNP assembly

Integration of mRNP formation and export

Cutting a Long Intron Short: Recursive Splicing and Its Implications

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