A simple answer for a splicing conundrum

Abstract

A Simple Answer for a Splicing Conundrum. Douglas L. Black The medieval philosopher William of Occam admonished that it is best to minimize the postulated entities needed to explain a system. This concept of choosing the simplest explanation of unknown phenomena is now known as the Principle of Parsimony or Occam's Razor. However, in biology, where systems tend to evolve towards states of greater complexity, Occam's Razor can be a dangerous tool. Most often the known components of a biological process increase with study. It is not always safe to assume a limited number of factors are involved. Sometimes though, we do find a simple explanation of a puzzling phenomenon that requires no new unknowns to be added to the model. Such an event is described in this issue of PNAS, where three groups nicely explain a long-standing puzzle in eukaryotic mRNA processing [1]. Specifically, they demonstrate a plausible mechanism for how exons are always linked in order during the pre-mRNA splicing process, without a single exon being skipped. Eukaryotic mRNAs are transcribed as long precursor molecules containing intervening sequences, or introns separating the coding or otherwise functional portions of the transcript called exons (Figure 1A). To form a mature mRNA ready for translation, the cell must precisely excise the introns and ligate the exons together. This process of pre-mRNA splicing is carried out in the cell nucleus by a large macromolecular complex called the spliceosome [2]. Components of the spliceosome recognize special sequences at the intron ends called splice sites. The 5' splice site (at the 5' end of the intron) is initially bound by the U1 snRNP, and the 3' splice site is bound by the protein U2 Auxiliary Factor (U2AF) [3, 4]. These components interact to bring the two ends of the intron together, before going on to assemble the rest of the spliceosome that ultimately catalyzes the cleavage/ligation reactions. Early on, two questions of how splice sites are chosen for pairing during splicing were seen as particularly mysterious [5-7]. First, introns can be very long (>1000 nt.) and have within them many copies of the splice site consensus sequences. It was not understood how the correct sites at the intron ends were recognized, while the other cryptic sites were avoided. Second, pre-mRNAs can contain many exons that must