Regulation of Gene Expression by Coupling of Alternative Splicing and NMD

Most human genes exhibit alternative splicing, but not all alternatively spliced transcripts produce functional proteins. Computational and experimental results indicate that roughly a third of reliably inferred alternative splicing events in humans result in mRNA isoforms that harbor a premature termination codon (PTC). These transcripts are predicted to be degraded by the NMD pathway. One potential explanation for this startling observation is that cells routinely link alternative splicing and NMD to regulate the abundance of mRNA transcripts. This mechanism, which we call “Regulated Unproductive Splicing and Translation” (RUST), has been experimentally shown to regulate the expression of a wide variety of genes in many organisms from yeast to humans. It is frequently employed to autoregulate proteins that affect the splicing process itself. Thus, alternative splicing and NMD, acting together, play an important and widespread role in regulating gene expression.