Abstract
More than 5% of alternatively spliced internal exons in the human genome are derived from Alu elements in a process termed exonization. Alus are comprised of two homologous arms separated by an internal polypyrimidine tract (PPT). In most exonizations, splice sites are selected from within the same arm. We hypothesized that the internal PPT may prevent selection of a splice site further downstream. Here, we demonstrate that this PPT enhanced the selection of an upstream 5′ splice site (5′ss), even in the presence of a stronger 5′ss downstream. Deletion of this PPT shifted selection to the stronger downstream 5′ss. This enhancing effect depended on the strength of the downstream 5′ss, on the efficiency of base-pairing to U1 snRNA, and on the length of the PPT. This effect of the PPT was mediated by the binding of TIA proteins and was dependent on the distance between the PPT and the upstream 5′ss. A wide-scale evolutionary analysis of introns across 22 eukaryotes revealed an enrichment in PPTs within ∼20 nt downstream of the 5′ss. For most metazoans, the strength of the 5′ss inversely correlated with the presence of a downstream PPT, indicative of the functional role of the PPT. Finally, we found that the proteins that mediate this effect, TIA and U1C, and in particular their functional domains, are highly conserved across evolution. Overall, these findings expand our understanding of the role of TIA1/TIAR proteins in enhancing recognition of exons, in general, and Alu exons, in particular.
Highlights
Alternative splicing of mRNA precursors allows the synthesis of multiple mRNA isoforms from a single primary transcript [1,2,3,4]
Alu elements are prone to undergo exonization: more than 5% of alternatively spliced internal exons in the human genome originate from Alu elements
A typical Alu element is,300 nucleotides long, consisting of two arms separated by a polypyrimdine tract (PPT)
Summary
Alternative splicing of mRNA precursors allows the synthesis of multiple mRNA isoforms from a single primary transcript [1,2,3,4]. Recent analyses indicate that the majority of human genes are alternatively spliced, contributing significantly to human transcriptome diversity [5,6]. The spliceosome consists of five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) and over 200 associated proteins. The 59ss consensus sequence in higher eukaryotes is comprised of nine bases that bridge the exon-intron boundary; this region is bound by a complementary region along the RNA component of the U1 snRNP. In most pre-mRNAs the base pairing of U1 snRNP and 59ss is not perfect. Increased complementarity between U1 snRNP and the 59ss strongly contributes to 59ss selection [8,9] and can shift the splicing pattern from alternative to constitutive [10,11]
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