A simple principle to explain the evolution of pre-mRNA splicing.

One of the most surprising discoveries of molecular biology was the realization that eukaryotic messenger RNAs (mRNA) are usually transcribed as precursors containing internal noncoding sequences (introns) that need to be excised to generate translatable mRNAs. The process of intron removal (or pre-mRNA splicing) requires precise definition of the intron boundaries. This is achieved in part through base-pairing interactions involving specific U-rich small nuclear RNAs (U snRNAs) and particular intronic sequences near the splice sites (for review, see Valadkhan 2005). While the U snRNA sequences involved in these interactions have been conserved during evolution, pre-mRNA splicing signals are conserved in introns of the yeast Saccharomyces cerevisiae, but they are significantly more variable in higher eukaryotes (Fig. 1A; for review, see Ast 2004). To compensate for this sequence divergence and consequent loss of base-pairing to U snRNAs, recognition of higher eukaryotic introns often relies on additional sequences located in exons and introns that act as splicing enhancers. One class of factors recognizing enhancer sequences are serine–arginine-rich (SR) proteins, which are a diverse family of splicing factors and regulators containing arginine–serine-rich (RS) domains. In contrast, SR-like proteins and RS domains are rare in budding yeast and have not been implicated in the splicing process. Results from Shen and Green (2006) in this issue of Genes & Development indicate that SR proteins allow for higher sequence variation at splicing signals because their RS domains interact with double-stranded RNA (dsRNA) and help to stabilize base-pairing interactions. Shen and Green (2006) show that yeast introns can afford sequence variation at splice sites provided that an heterologous RS domain is targeted to their vicinity. Conversely, the requirement for an SR protein to remove a higher eukaryotic intron can be waived by increasing the complementarity of a splicing signal with a particular U snRNA. These observations offer a surprisingly simple rationale for the concerted evolution of splicing signals and transacting factors and have important implications for understanding alternative splicing regulation. Sustaining this picture is the intriguing property of phosphorylated RS domains to recognize short (often imperfectly basepaired) stretches of dsRNA, which poses an interesting additional question for structural biologists.