Splicing and 3′ end formation in the definition of nonsense-mediated decay-competent human β-globin mRNPs

Premature translation termination codons are common causes of genetic disorders. mRNAs with such mutations are degraded by a surveillance mechanism termed nonsense-mediated decay (NMD), which represents a phylogenetically widely conserved posttranscriptional mechanism for the quality control of gene expression. How NMD-competent mRNPs are formed and specified remains a central question. Here, we have used human beta -globin mRNA as a model system to address the role of splicing and polyadenylation for human NMD, We show that (i) splicing is an indispensable component of the human beta -globin NMD pathway, which cannot be compensated for by exonic beta -globin 'failsafe' sequences; (ii) the spatial requirements of human beta -globin NMD, as signified by the maximal distance of the nonsense mutation to the final exon-exon junction, are less constrained than in yeast; and (iii) non-polyadenylated mRNAs with a histone 3' end are NMD competent. Thus, the formation of NMD-competent mRNP particles critically depends on splicing but does not require the presence of a poly(A) tail.