Exon sequences at the splice junctions affect splicing fidelity and alternative splicing

Crotti, Luciana B.; Horowitz, David S.

doi:10.1073/pnas.0907948106

Cited by 24 publications

(31 citation statements)

References 39 publications

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“…Given the presented results on transcript variants and the database annotation discrepancies for this genomic region, the mechanism possibly lies in alternative splicing. This would not be the first reported case of an exonic SNP affecting splicing (Crotti & Horowitz , Pagani & Baralle ) and, consequently, gene expression efficiency (Beer & Sahin‐Toth ). Furthermore, here we show that variations of the microsatellite CLF20OXTR1 in the 3′ UTR also interfere with gene expression.…”

Section: Discussionmentioning

confidence: 76%

Lessons from the canine Oxtr gene: populations, variants and functional aspects

Bence

Marx

Szantai

et al. 2016

Genes Brain and Behavior

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Oxytocin receptor (OXTR) acts as a key behavioral modulator of the central nervous system, affecting social behavior, stress, affiliation and cognitive functions. Variants of the Oxtr gene are known to influence behavior both in animals and humans, however, canine Oxtr polymorphisms are less characterized in terms of possible relevance to function, selection criteria in breeding and domestication. In this report, we provide a detailed characterization of common variants of the canine Oxtr gene. In particular, (1) novel polymorphisms were identified by direct sequencing of wolf and dog samples, (2) allelic distributions and pairwise linkage disequilibrium patterns of several canine populations were compared, (3) neighbor joining tree based on common SNPs was

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Section: Discussionmentioning

confidence: 76%

Lessons from the canine Oxtr gene: populations, variants and functional aspects

Bence

Marx

Szantai

et al. 2016

Genes Brain and Behavior

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“…These data hint at a failure in vital spliceosomal interactions of these nonfunctional variants. In budding yeast ScPrp18, the CR loop is proposed, in a context-dependent manner, to improve interactions between exonic residues and budding yeast U5 snRNA loop 1 (13)(14)(15)45). We speculate that the critical roles for SpPrp18 helix 5 and CR domain may also be to improve U5 loop 1 with exonic sequence interactions.…”

Section: Discussionmentioning

confidence: 98%

The Fission Yeast Pre-mRNA-processing Factor 18 (prp18+) Has Intron-specific Splicing Functions with Links to G1-S Cell Cycle Progression

Vijaykrishna¹,

Melangath²,

Kumar³

et al. 2016

Journal of Biological Chemistry

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Edited by Linda SpremulliThe fission yeast genome, which contains numerous short introns, is an apt model for studies on fungal splicing mechanisms and splicing by intron definition. Here we perform a domain analysis of the evolutionarily conserved Schizosaccharomyces pombe pre-mRNA-processing factor, SpPrp18. Our mutational and biophysical analyses of the C-terminal ␣-helical bundle reveal critical roles for the conserved region as well as helix five. We generate a novel conditional missense mutant, spprp18-5. To assess the role of SpPrp18, we performed global splicing analyses on cells depleted of prp18 ؉ and the conditional spprp18-5 mutant, which show widespread but intron-specific defects. In the absence of functional SpPrp18, primer extension analyses on a tfIId ؉ intron 1-containing minitranscript show accumulated pre-mRNA, whereas the lariat intron-exon 2 splicing intermediate was undetectable. These phenotypes also occurred in cells lacking both SpPrp18 and SpDbr1 (lariat debranching enzyme), a genetic background suitable for detection of lariat RNAs. These data indicate a major precatalytic splicing arrest that is corroborated by the genetic interaction between spprp18-5 and spprp2-1, a mutant in the early acting U2AF59 protein. Interestingly, SpPrp18 depletion caused cell cycle arrest before S phase. The compromised splicing of transcripts coding for G 1 -S regulators, such as Res2, a transcription factor, and Skp1, a regulated proteolysis factor, are shown. The cumulative effects of SpPrp18-dependent intron splicing partly explain the G 1 arrest upon the loss of SpPrp18. Our study using conditional depletion of spprp18 ؉ and the spprp18-5 mutant uncovers an intron-specific splicing function and early spliceosomal interactions and suggests links with cell cycle progression.Pre-mRNA splicing, a fundamental step in the processing of nascent eukaryotic RNA polymerase II transcripts, achieves precise excision of introns coupled with exon ligation to generate functional mRNAs. The spliceosome, which is composed of five U snRNPs 7 and Ͼ100 auxiliary proteins, assembles onto cis splicing signals, namely the 5Ј splice site (5Јss), the branch point nucleotide, the 3Ј splice site (3Јss), and polypyrimidine (Pyn) tracts. The spliceosomal catalytic core consists of the U2, U5, and U6 snRNPs and accessory proteins. This complex mediates the two trans-esterification reactions required for splicing to occur. First, the 5Јss is cleaved to yield the branched lariat intron-exon 2 and exon 1 intermediates, followed by the second reaction, where the 3Јss is cleaved, the exons are joined, and lariat intron is excised (1, 2).Genetic and biochemical analyses in budding yeast and biochemical studies with mammalian cell extracts have established a network of interactions among factors that act at the second step of splicing (i.e. Prp8, Prp16, Prp17, Prp18, Slu7, and Prp22) (3-8). PRP18, a non-essential budding yeast gene, encodes a U5 snRNP-associated factor. Prp18 has been analyzed extensively in budding yeast and human cell...

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“…In contrast, the identification of the of its multiple occurrence and the lack of a clear selector comparable to U1. Several intron branch site (BS) or from a downstream pyrimidine-rich track (Patterson and Guthrie, 1991;Smith et al, 1993) (Goguel and Rosbash, 1993), or with the downstream exon (Crotti and Horowitz, 2009); distance from the BS (Cellini et al, 1986;Luukkonen and Seraphin, 1997); and interactions with splicing factors (Smith et al, 2008;Umen and Guthrie, 1995). But despite these required to fully decode eukaryotic genomes.…”

Section: Introductionmentioning

confidence: 99%

Deciphering 3′ss Selection in the Yeast Genome Reveals an RNA Thermosensor that Mediates Alternative Splicing

et al. 2011

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Poor understanding of the spliceosomal mechanisms to select intronic 3' ends (3'ss) is a major obstacle to deciphering eukaryotic genomes. Here, we discern the rules for global 3'ss selection in yeast. We show that, in contrast to the uniformity of yeast splicing, the spliceosome uses all available 3'ss within a distance window from the intronic branch site (BS), and that in ∼70% of all possible 3'ss this is likely to be mediated by pre-mRNA structures. Our results reveal that one of these RNA folds acts as an RNA thermosensor, modulating alternative splicing in response to heat shock by controlling alternate 3'ss availability. Thus, our data point to a deeper role for the pre-mRNA in the control of its own fate, and to a simple mechanism for some alternative splicing.

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Exon sequences at the splice junctions affect splicing fidelity and alternative splicing

Cited by 24 publications

References 39 publications

Lessons from the canine Oxtr gene: populations, variants and functional aspects

Lessons from the canine Oxtr gene: populations, variants and functional aspects

The Fission Yeast Pre-mRNA-processing Factor 18 (prp18+) Has Intron-specific Splicing Functions with Links to G1-S Cell Cycle Progression

Deciphering 3′ss Selection in the Yeast Genome Reveals an RNA Thermosensor that Mediates Alternative Splicing

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