Nonsense-mediated mRNA decay in mammals

Nonsense-mediated mRNA decay (NMD) in mammalian cells generally degrades mRNAs that terminate translation more than 50-55 nucleotides upstream of a splicing-generated exon-exon junction (reviewed in Maquat, 2004a; Nagy and Maquat, 1998). Notably, dependence on exon-exon junctions distinguishes NMD in mammalian cells from NMD in all other organisms that have been examined, including Saccharomyces cerevisiae and Drosophila melanogaster (reviewed in Maquat, 2004b). NMD downregulates spliced mRNAs that prematurely terminate translation so production of the potentially toxic truncated proteins that they encode. NMD also downregulates naturally occurring mRNAs, such as an estimated one-third of alternatively spliced mRNAs, certain selenoprotein mRNAs, some mRNAs that have upstream open reading frames, and some mRNAs that contain an intron within the 3′ untranslated region (Hillman et al., 2004; Mendell et al., 2004; Moriarty et al., 1998). In fact, it is thought that NMD has been maintained throughout evolution not only because it degrades transcripts that are the consequence of routine abnormalities in gene expression but also because it is widely used to achieve proper levels of gene expression. Although disease-associated mutations that result in the premature termination of translation led to the discovery of NMD, it is not likely that this type of mutation ever drove significant evolutionary selection. Nevertheless, some of these mutations nicely illustrate the importance of NMD. For example, nonsense mutations within the last exon of the human β-globin gene do not elicit NMD because there is no downstream exon-exon junction. As a consequence, the resulting truncated β-globin has near-normal abundance, fails to properly associate with α-globin and causes a dominantly inherited form of what is otherwise (e.g. for nonsense codons