The Coupling of Alternative Splicing and Nonsense-Mediated mRNA Decay

Abstract

M ost human genes exhibit alternative splicing, but not all alternatively spliced transcripts produce functional proteins. Computational and experimental results indicate that a substantial fraction of 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 nonsense-mediated mRNA decay (NMD) pathway. One explanation for the abundance of PTC-containing isoforms is that they represent splicing errors that are identified and degraded by the NMD pathway. Another potential explanation for this startling observation is that cells may 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 expression of a wide variety of genes in many organisms from yeast to human. It is frequently employed for autoregulation of proteins that affect the splicing process itself. Thus, alternative splicing and NMD act together to play an important role in regulating gene expression.

Intron retention generates ANKRD1 splice variants that are co-regulated with the main transcript in normal and failing myocardium

“…Often, retention of internal introns restricts the export of these mRNAs and makes them the targets for degradation by the nonsense-mediated mRNA decay (NMD) pathway, particularly if they contain premature TC (Blencowe, 2006;Lareau et al, 2007). We have employed a variety of complimentary approaches to demonstrate that the identified intron-retaining ankrd1 transcripts are functionally intact and efficiently translated into protein in vitro (see Fig.…”

“…Conflicting hypotheses regarding the role of alternative splicing-NMD coupling in regulation of gene expression exist (Lareau et al, 2007). As previously suggested, NMD activated by alternative splicing events can represent a mechanism by which expression of a given gene could be down-regulated in a tissue-restricted manner (Alonso, 2005).…”

Regulating the regulators: Serine/arginine‐rich proteins under scrutiny

“…In particular, alternative splicing of these regions is involved in the generation of non-sense mediated decay (NMD)-sensitive isoforms, either through the incorporation of premature translation termination codons (PTC) or the generation of exon-exon junctions downstream the canonical stop codon. This phenomenon that couples alternative splicing to NMD (AS-NMD) was described for several genes, being particularly frequent and conserved in SR genes and providing a regulatory mechanism by which splicing factors could exercise their function as alternative splicing regulators to maintain their expression levels (25). Furthermore, the Brenner laboratory has demonstrated the existence of unproductive splicing in 11 human SR genes.…”

Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay

“…Microarray profiling combined with bioinformatics has indicated that depletion of mammalian NMD factors substantially increases levels of predicted PTC-containing splice variants for a relatively small proportion of the total number of genes containing AS events capable of PTC introduction (12)(13)(14)(15)(16). To date, the genes associated with the greatest changes in PTC-containing splice variant transcripts upon NMD disruption include those encoding splicing factors or other RNA-binding/ processing proteins (17)(18)(19). Increasing evidence indicates that AS-coupled NMD of splicing factor transcripts may play an important role in both autoregulation and cross-regulation of these and other RNA processing proteins.…”