Execution of nonsense-mediated mRNA decay: what defines a substrate?

The nonsense-mediated mRNA decay (NMD) pathway targets mRNAs with premature termination codons as well as a subset of normal mRNAs for rapid decay. Emerging evidence suggests that mRNAs become NMD substrates based on the composition of the mRNP downstream of the translation termination event, which either stimulates or antagonizes recruitment of the NMD machinery. The NMD mRNP subsequently undergoes several remodeling events, which involve hydrolysis of ATP by the NMD factor Upf1 and in metazoans, a phosphorylation/dephosphorylation cycle of Upf1 mediated by Smg proteins. This leads to mRNA decay following translational repression. Recent evidence suggests that in Drosophila and human cells, decay is initiated by the endonuclease Smg6.