Translation of an improperly processed mRNA could lead to production of an abnormal protein that interferes with the gene’s normal function. This effect would be equivalent to that of a dominant-negative mutation, discussed in Chapter 6 (see Figure 6-41). Several mechanisms, collectively termed mRNA surveillance, help cells avoid the translation of improperly processed mRNA molecules. We have previously mentioned two such surveillance mechanisms: the recognition of improperly processed pre-mRNAs in the nucleus and their degradation by nuclear exosomes, and the general restriction against nuclear export of incompletely spliced pre-mRNAs that remain associated with a snRNP.

Another surveillance mechanism, called nonsense-mediated decay (NMD), causes degradation of mRNAs in which one or more exons have been incorrectly spliced. Such incorrect splicing often alters the open reading frame of the mRNA 3′ to the improper exon-exon junction, resulting in the introduction of an out-of-frame missense mutation and an incorrect stop codon. For nearly all properly spliced mRNAs, the stop codon is in the last exon. Nonsense-mediated decay results in the rapid degradation of mRNAs with stop codons that occur before the last exon-exon junction, since in most cases, such mRNAs arise from errors in RNA splicing. However, NMD can also result from a mutation creating a stop codon within a gene or a frame-shifting deletion or insertion. NMD was initially discovered during the study of patients with β⁰-thalassemia, who produce a low level of β-globin protein associated with a low level of β-globin mRNA (Figure 10-34).

A search for possible molecular signals that might indicate the positions of exon-exon junctions in a processed mRNA led to the discovery of exon-junction complexes. As noted already, these complexes of several proteins (including Y14, Magoh, eIF4IIIA, UPF2, UPF3, and REF) bind about 20 nucleotides 5′ to an exon-exon junction following RNA splicing and stimulate export of mRNPs from the nucleus by interacting with the mRNP exporter (see Figure 10-23). Analysis of yeast mutants indicated that one of the proteins in exon-junction complexes (UPF3) functions in nonsense-mediated decay. In the cytoplasm, UPF3 interacts with a protein (UPF1) and a protein kinase (SMG1) that phosphorylates it, causing the mRNA to associate with P bodies, repressing translation and inducing degradation of the mRNA. An additional protein (UPF2) associated with the exon-junction complex binds a P body–associated deadenylase complex that rapidly removes the poly(A) tail from the associated mRNA, leading to its decapping and degradation by the P body–associated 5′→3′ exoribonuclease XRN1 (see Figure 10-24). In the case of a properly spliced mRNA, the mRNP exporter associated with the nuclear cap-binding complex is exported through a nuclear pore complex, thereby protecting the mRNA from degradation. The exon-junction complexes are thought to be dislodged from the mRNA by passage of the first “pioneer” ribosome to translate the mRNA. However, for mRNAs with a stop codon before the final exon-exon junction, one or more exon-junction complexes remain associated with the mRNA, resulting in nonsense-mediated decay (Figure 10-35a). Alternative mechanisms lead to the inhibition of translation and degradation of mRNAs that were polyadenylated prematurely (non-stop decay) (Figure 10-35b) or that contain damaged bases or stable secondary structures that block ribosomal translocation along the mRNA (no-go decay) (Figure 10-35c).

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