Exon definition

Traditionally, a splicing construct contains an intron flanked by two exons. However, interactions across the exons play an important role in spliceosome assembly, a phenomenon termed exon definition.6 The presence of an upstream 3 -splice site generally stimulates the function of a weak downstream 5 -splice site. Similarly, a downstream 5 -splice site induces the usage of a weak upstream 3 -splice site. In this transactivation model, the 5 -cap structure of the first exon and the polyadenylation site in the terminal exons act as 3 - and 5 -splice sites, respectively, in promoting the spliceosome assembly. This view is reinforced by the observation that less efficiently spliced introns may be stimulated by moving the 5 -cap closer to the 5 -splice site or by inserting a functional 5 -splice- or polyadenylation site in the 3 -exon. However, exon definition seems only to play a minor role for efficiently spliced introns in vitro. 

SR Proteins Contribute to Exon Definition in Long Pre-mRNAs... 

Several kinds of studies suggest that transcription and RNA processing occur largely within discrete foci within the nucleus of eukaryotic cells. For instance, digital Imaging microscopy of human fibroblasts reveals that most of the nuclear polyadenylated RNA (i.e., unspllced and partially spliced pre-mRNA and nuclear mRNA) Is localized In about 100 foci (Figure 12-13). An SR protein Involved In exon definition (SC-35) is localized to the center of these same loci. 

FIGURE 8 The exon definition model. Exons in a precursor-RNA are recognized as units by U2 snRNP (U2) binding to the 3 splice site and U1 snRNP (U1) binding to the downstream 5 splice site. Subsequently adjacent exons are defined across the intron. In both recognition steps SR proteins function as bridging proteins. 

Subsequently, serum lipid and lipoprotein profiles were obtained 70 mg/dL total cholesterol (normal is 130-200 mg/dL), 1 mg/dL HDL cholesterol (optimal is > 60 mg/dL), 180 mg/dL triglycerides (normal is 100-150 mg/dL), and less than 5 mg/dL apolipoprotein A-I (apoA-I normal is 140 mg/dL). Cholesterol efflux from patient skin fibroblasts to apoA-I, the main protein component of HDL, was reduced to 30% of normal. These results indicated Tangier disease, the definitive diagnosis of which was made when the sequencing of the ATP-binding cassette transporter A1 (ABCA /) gene revealed a nonsense mutation within exon 12. 

Goren A, Ram O, Amit M, Keren H, Lev-Maor G et til (2006) Comparative analysis identifies exonic spUdng regulatoiy sequences - The complex definition of enhancers and silencers. Mol Cell 22 769-781... 

Zhang XH, Chasin LA (2004) Computational definition of sequence motifs governing constitutive exon splicing. Genes Dev 18 1241-1250... 

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