SpliceDisease database: linking RNA splicing and disease

Wang, Juan; Zhang, Jie; Li, Kaibo; Zhao, Wei; Cui, Qinghua

doi:10.1093/nar/gkr1171

Cited by 52 publications

(44 citation statements)

References 35 publications

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“…RNA splicing is a critical posttranscriptional regulatory mechanism, and ∼60% of noninfectious human diseases arise from splicing disorders; thus, the study of pre-mRNA splicing mechanisms has a high priority for human health (37). Splicing involves highly dynamic, organized, and exceptional compositional and structural rearrangements within the spliceosome during complex assembly, catalytic activation, and disassembly (38).…”

Section: Discussionmentioning

confidence: 99%

“…Splicing involves highly dynamic, organized, and exceptional compositional and structural rearrangements within the spliceosome during complex assembly, catalytic activation, and disassembly (38). Therefore, any mutations in the genes involved in RNA splicing machinery may give rise to serious diseases (37). For example, perturbation of the SMN gene results in widespread splicing defects and thus causes spinal muscular atrophy, a motor neuron disease (39).…”

Section: Discussionmentioning

confidence: 99%

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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%

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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“…AS is one of the main control mechanisms for cell phenotype, and a process deregulated in disease. There are over 2000 splicing mutations known, involving 303 genes and implicated in 370 diseases [8] . Therefore it has become essential to study how this process is regulated, and how it can become deregulated in disease.…”

Section: Asmentioning

confidence: 99%

Modulators of alternative splicing as novel therapeutics in cancer

Oltean¹

2015

WJCO

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have now conclusively shown that more than 90% of genes are alternatively spliced in humans. This makes AS one of the main drivers of proteomic diversity and, consequently, determinant of cellular function repertoire. Unsurprisingly, given its extent, numerous splice isoforms have been described to be associated with several dise ases including cancer. Many of them have antagonistic functions, e.g. , pro and antiangiogenic or pro and antiapoptotic. Additionally several splice factors have been recently described to have oncogene or tumour suppressors activities, like SF3B1 which is frequently mutated in myelodysplastic syndromes. Beside the implications for cancer pathogenesis, deregulated AS is recognized as one of the novel areas of cell biology where therapeutic manipulations may be designed. This editorial discusses the possibilities of manipulation of AS for therapeutic benefit in cancer. Approaches involving the use of oligonucleotides as well as small molecule splicing modulators are presented as well as thoughts on how specificity might be accomplished in splicing therapeutics. Core tip: Genomewide studies have recently shown that more than 90% of genes are alternatively spliced in humans. This makes alternative splicing (AS) one of the main drivers of proteomic diversity. Numerous splice isoforms have been described to be associated with cancer. Additionally several splice factors have been shown to have oncogene or tumour suppressors activities. Beside the implications for cancer pathogenesis, deregulated AS is recognized as one of the novel areas of cell biology where therapeutic manipulations may be designed. This editorial discusses the possibilities of manipulation of AS for therapeutic benefit in cancer. Modulators of alternative splicing as novel therapeutics in cancer AbstractAlternative splicing (AS), the process of removing introns from premRNA and rearrangement of exons to give several types of mature transcripts, has been described more than 40 years ago. However, until recently, it has not been clear how extensive it is. Genomewide studies

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“…The result of such aberrant splicing will be evident from the transcriptome data. Publicly available databases with known alternative splicing events [82], novel pathogenic exon boundaries [106], as well as resources integrating RNA splicing mutations and various diseases [107] are invaluable tools in analyzing cancer genomes.…”

Section: Data Interpretationmentioning

confidence: 99%