Evo Devo

Evolutionary development - at the biological interface between genetic regulatory mechanisms and biological evolution.

alternative 3' splicing

AS can also be attained by altering the position of the splice acceptor, alternative 3' splice site (3'AS). Together with alternative donor 5' splice site (5'AS), 3'AS contributes 25% of all AS events conserved between humans and mice (4).

"Recently, Hiller et al. (9) reported a widespread occurrence of a NAGNAG 3' acceptor splice site motif in the human genome. The NAGNAG motif includes two 3' splice site motifs in tandem and thus has the potential of producing mRNA isoforms which differ by a 3 nt sequence (NAG). Based on their analysis, Hiller et al. (9) suggested that the NAGNAG motif, which can insert or delete a single amino acid in the protein, is present in 30% of human genes and is functional in at least 5% of the genes. In addition it has been observed that alternative spliced isoforms, resulting from the NAGNAG motif are differentially expressed in human and mouse tissues (9,10).

...findings suggest that the selection of an acceptor site (3'AS) depends on the sequence environment, and can be altered by subtle changes such as point mutations. This is consistent with other studies showing that the pattern of AS can be altered by mutations in exonic splicing enhancer sites (ESEs) and exonic splicing silencer [sic] sites (ESSs) (16).

... by itself, the NAGNAG motif is not sufficient for AS. Nevertheless, analysis of a subset of the NAGNAG sites confirmed by expressed sequence tag (EST) data to be alternatively spliced shows that they encompass several characteristics of other known AS events. Comparison between the constitutively and alternatively spliced NAGNAG sites revealed that they differ principally by three major properties: (i) the sequence and evolutionary conservation of the NAGNAG motif, (ii) the conservation of intron sequences flanking the NAGNAG site, and (iii) the abundance of known cis-regulatory elements in the neighboring regions of the 3' splice sites. " [Alternative splicing regulation at tandem 3' splice sites]

Regulation of alternative 3' splice site selection by constitutive splicing factors.
Polypyrimidine tract binding protein (PTB) was found to inhibit the splicing of introns containing a strong binding site for this factor. However, the inhibitory effect of PTB could be partially reversed if pre-mRNAs were preincubated with U2 auxiliary factor (U2AF) prior to splicing in PTB-supplemented extracts. For alpha-tropomyosin, regulation of splicing by PTB and U2AF primarily affected the joining of exons 1-3 with no dramatic increases in 1-2 splicing being detected. Preincubation of pre-mRNAs with SR proteins led to small increases in 1-2 splicing. However, if pre-mRNAs were preincubated with SR proteins followed by splicing in PTB-supplemented extracts, there was a nearly complete reversal of the normal 1-2 to 1-3 splicing ratios. Thus, multiple pairwise, and sometimes antagonizing, interactions between constitutive pre-mRNA splicing factors and the pre-mRNA can regulate 3' splice site selection.
Lin CH, Patton JG. Regulation of alternative 3' splice site selection by constitutive splicing factors. RNA. 1995 May;1(3):234-45.


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