NMD: At the crossroads between translation termination and ribosome recycling

Nonsense-mediated mRNA decay (NMD) is one of three regulatory mechanisms that monitor the cytoplasm for aberrant mRNAs. NMD is usually triggered by premature translation termination codons that arise from mutations, transcription errors, or inefficient splicing, but which also occur in transcripts with alternately spliced isoforms or upstream open reading frames, or in the context of long 3'-UTRs. This surveillance pathway requires detection of the nonsense codon by the eukaryotic release factors (eRF1 and eRF3) and the activities of the Upf proteins, but the exact mechanism by which a nonsense codon is recognized as premature, and the individual roles of the Upf proteins, are poorly understood. In this review, we highlight important differences between premature and normal termination. Based on our current understanding of normal termination and ribosome recycling, we propose a similar mechanism for premature termination events that includes a role for the Upf proteins. In this model, the Upf proteins not only target the mRNA and nascent peptide for degradation, but also assume the role of recycling factors and rescue a ribosome stalled at a premature nonsense codon. The ATPase and helicase activities of Upf1, with the help of Upf2 and Upf3, are thus thought to be the catalytic force in ribosome subunit dissociation and ribosome recycling at an otherwise poorly dissociable termination event. While this model is somewhat speculative, it provides a unified vision for current data and a direction for future research.