Enhancer-dependent 5′-Splice Site Control of fruitless Pre-mRNA Splicing

Lam, Bianca J.; Bakshi, Arati; Ekinci, Fatma Yeşim; Webb, Jenny; Graveley, Brenton R.; Hertel, Klemens J.

doi:10.1074/jbc.m301036200

Cited by 32 publications

(22 citation statements)

References 60 publications

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“…Likewise, the fruitless repeat element (fruRE) from Drosophila consists of three 13-nt repeat elements. In this case, only one repeat element within fruRE is necessary and sufficient to activate the female-specific splice site (Lam et al 2003). fruRE and dsxRE function similarly in activating 59ss and 39ss, respectively, and these ESE complexes are capable of recruiting targets that contain multiple spliceosomal components required for the initial recognition of 59ss and 39ss.…”

Section: Discussionmentioning

confidence: 99%

Multisite and bidirectional exonic splicing enhancer in CD44 alternative exon v3

Vela¹,

Hilari²,

Roca³

et al. 2007

RNA

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The human CD44 gene encodes multiple isoforms of a transmembrane protein that differ in their extracellular domains as a result of alternative splicing of its variable exons. Expression of CD44 is tightly regulated according to the type and physiological status of a cell, with expression of high molecular weight isoforms by inclusion of variable exons and low molecular weight isoforms containing few or no variable exons. Human CD44 variable exon 3 (v3) can follow a specific alternative splicing route different from that affecting other variable exons. Here we map and functionally describe the splicing enhancer element within CD44 exon v3 which regulates its inclusion in the final mRNA. The v3 splicing enhancer is a multisite bipartite element consisting of a tandem nonamer, the XX motif, and an heptamer, the Y motif, located centrally in the exon. Each of the three sites of this multisite enhancer partially retains its splicing enhancing capacity independently from each other in CD44 and shows full enhancing function in gene contexts different from CD44. We further demonstrate that these motifs act cooperatively as at least two motifs are needed to maintain exon inclusion. Their action is differential with respect to the splice-site target abutting v3. The first X motif acts on the 39 splice site, the second X motif acts on both splice sites (as a bidirectional exonic splicing enhancer), and the Y motif acts on the 59 splice site. We also show that the multisite v3 splicing enhancer is functional irrespective of flanking intron length and spatial organization within v3.

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Section: Discussionmentioning

confidence: 99%

Multisite and bidirectional exonic splicing enhancer in CD44 alternative exon v3

Vela¹,

Hilari²,

Roca³

et al. 2007

RNA

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“…In the nervous system, TRA-2 isoforms and TRA proteins direct female-specific utilization of an alternative 5' splice site in fruitless pre-mRNA resulting in sex-specific expression of Fruitless isoforms, which in turn promote the development of innate sex-specific behaviour (Ryner et al, 1996). As in the case of dsx, this regulation depends on binding a specific set of TRA/TRA-2 binding sites in the fru pre-mRNA (Heinrichs et al, 1998, Lam et al, 2003. Both TRA-2 226 and TRA-2 179 are expressed in the male germ line, but only the former is necessary and sufficient for male fertility, acting independently of TRA and affecting sex-specific processing of pre-mRNA from exuperantia (exu), alternative testis transcripts (att), and tra-2 itself (Hazelrigg and Tu, 1994, Madigan et al, 1996, McGuffin et al, 1998.…”

Section: Introductionmentioning

confidence: 99%

Ceratitis capitata transformer-2 gene is required to establish and maintain the autoregulation of Cctra, the master gene for female sex determination

Salvemini¹,

Robertson²,

Aronson³

et al. 2009

Int. J. Dev. Biol.

138

237

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In Drosophila melanogaster, transformer-2 (TRA-2) which is a non-sex-specific auxiliary splicing factor, is required to promote female sexual differentiation by interaction with the female-specific TRA. The two proteins positively regulate the splicing of both doublesex (dsx) and fruitless (fru) pre-mRNAs, which in turn regulate phenotypic and behavioural sexual dimorphism. In the Mediterranean fruitfly Ceratitis capitata, the female-specific CcTRA is similarly required not only for Ccdsx splicing, but also to exert a novel autoregulatory function that consists of promoting female-specific splicing of Cctra pre-mRNA. This study reports the isolation and functional analysis of the C. capitata homologue of the Drosophila transformer-2 gene (Cctra-2). Transient RNAi against Cctra-2 during embryonic development causes the full sex reversal of XX flies in adult fertile pseudo-males, as well as changes in the splicing pattern of Cctra, Ccdsx and Ccfruitless (Ccfru). We propose that: 1) Cctra-2, as in Drosophila, is necessary for promoting Ccdsx and putative Ccfru pre-mRNA female-specific splicing and that 2) unlike in Drosophila, Cctra-2 appears to be necessary for establishing female sex determination in early XX embryos and for maintaining the positive feedback regulation of Cctra during development.

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“…1A). Each pre-mRNA harbors the same weak 5Ј and 3Ј splice sites that require the activities of ESEs for recognition in their natural context (20,21). Because splicing factors present in HeLa cell nuclear extracts activate the ESEs used (21), the presence of functional or mutant enhancer elements within each test substrate determine its splicing efficiency.…”

Section: Switch Of Splice-site Recognition From Cross-intron Interactmentioning

confidence: 99%

The architecture of pre-mRNAs affects mechanisms of splice-site pairing

Fox-Walsh

Dou

Lam

et al. 2005

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

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227

266

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The exon͞intron architecture of genes determines whether components of the spliceosome recognize splice sites across the intron or across the exon. Using in vitro splicing assays, we demonstrate that splice-site recognition across introns ceases when intron size is between 200 and 250 nucleotides. Beyond this threshold, splice sites are recognized across the exon. Splice-site recognition across the intron is significantly more efficient than splice-site recognition across the exon, resulting in enhanced inclusion of exons with weak splice sites. Thus, intron size can profoundly influence the likelihood that an exon is constitutively or alternatively spliced. An EST-based alternative-splicing database was used to determine whether the exon͞intron architecture influences the probability of alternative splicing in the Drosophila and human genomes. Drosophila exons flanked by long introns display an up to 90-foldhigher probability of being alternatively spliced compared with exons flanked by two short introns, demonstrating that the exon͞ intron architecture in Drosophila is a major determinant in governing the frequency of alternative splicing. Exon skipping is also more likely to occur when exons are flanked by long introns in the human genome. Interestingly, experimental and computational analyses show that the length of the upstream intron is more influential in inducing alternative splicing than is the length of the downstream intron. We conclude that the size and location of the flanking introns control the mechanism of splice-site recognition and influence the frequency and the type of alternative splicing that a pre-mRNA transcript undergoes.alternative splicing ͉ bioinformatics ͉ EST database ͉ intron length P re-mRNA splicing is an essential process that accounts for many aspects of regulated gene expression. Of the Ϸ25,000 genes encoded by the human genome (1), Ͼ60% are believed to produce transcripts that are alternatively spliced. Thus, alternative splicing of pre-mRNAs can lead to the production of multiple protein isoforms from a single pre-mRNA, exponentially enriching the proteomic diversity of higher eukaryotic organisms (2, 3). Because regulation of this process can determine when and where a particular protein isoform is produced, changes in alternative-splicing patterns modulate many cellular activities.The spliceosome assembles onto the pre-mRNA in a coordinated manner by binding to sequences located at the 5Ј and 3Ј ends of introns. Spliceosome assembly is initiated by the stable associations of the U1 small nuclear ribonucleoprotein particle with the 5Ј splice site, branch-point-binding protein͞SF1 with the branch point, and U2 snRNP auxiliary factor with the pyrimidine tract (4). ATP hydrolysis then leads to the stable association of U2 snRNP at the branch-point and functional splice-site pairing (5).Intron size has been correlated with rates of evolution (6) and the regulation of genome size (7,8). The exon͞intron architecture has also been shown to influence splice-site recognition (9-11)....

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Enhancer-dependent 5′-Splice Site Control of fruitless Pre-mRNA Splicing

Cited by 32 publications

References 60 publications

Multisite and bidirectional exonic splicing enhancer in CD44 alternative exon v3

Multisite and bidirectional exonic splicing enhancer in CD44 alternative exon v3

Ceratitis capitata transformer-2 gene is required to establish and maintain the autoregulation of Cctra, the master gene for female sex determination

The architecture of pre-mRNAs affects mechanisms of splice-site pairing

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