Abstract
Messenger RNA splicing is an essential and complex process for the removal of intron sequences. Whereas the composition of the splicing machinery is mostly known, the kinetics of splicing, the catalytic activity of splicing factors and the interdependency of transcription, splicing and mRNA 3′ end formation are less well understood. We propose a stochastic model of splicing kinetics that explains data obtained from high-resolution kinetic analyses of transcription, splicing and 3′ end formation during induction of an intron-containing reporter gene in budding yeast. Modelling reveals co-transcriptional splicing to be the most probable and most efficient splicing pathway for the reporter transcripts, due in part to a positive feedback mechanism for co-transcriptional second step splicing. Model comparison is used to assess the alternative representations of reactions. Modelling also indicates the functional coupling of transcription and splicing, because both the rate of initiation of transcription and the probability that step one of splicing occurs co-transcriptionally are reduced, when the second step of splicing is abolished in a mutant reporter.
Highlights
The splicing of precursor messenger RNA is an essential process in the expression of most eukaryotic genes
Each section of DNA can be occupied by at most one polymerase II (Pol II), and the progression of Pol II from the 59 to the 39 end of the gene is equated with successful extension of the transcript
Despite the biochemical and genetic evidence for multiple steps in the cycle of splicing events, previous in vivo studies of messenger RNA (mRNA) splicing kinetics have revealed simple first-order monomolecular reactions that exclude the action of a catalyst
Summary
The splicing of precursor messenger RNA (pre-mRNA) is an essential process in the expression of most eukaryotic genes. The five small nuclear ribonucleoproteins (snRNPs) and the many nonsnRNP-associated proteins that constitute the splicing machinery, assemble anew on each precursor RNA to form the spliceosome complex that catalyses the two chemical reactions of splicing [1]. Both the spliceosome components and the spliceosome assembly process are largely conserved between human and yeast. The wealth of knowledge of molecular interactions, obtained mainly through extensive biochemical and genetic analyses, has yet to be formalised as a systems model of transcription and splicing
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