Transcript selection and the recruitment of mRNA decay factors for NMD in Saccharomyces cerevisiae

In Saccharomyces cerevisiae, nonsense-mediated mRNA decay (NMD) requires Upf1p, Upf2p, and Upf3p to accelerate the decay rate of two unique classes of transcripts: (1) nonsense mRNAs that arise through errors in gene expression, and (2) naturally occurring transcripts that lack coding errors but have built-in features that target them for accelerated decay (error-free mRNAs). NMD can trigger decay during any round of translation and can target Cbc-bound or elF-4E-bound transcripts. Extremely low concentrations of the Upf proteins relative to the total pool of transcripts make it difficult to understand how nonsense transcripts are selectively recruited. To stimulate debate, we propose two alternative mechanisms for selecting nonsense transcripts for NMD and for assembling components of the surveillance complex, one for the first (pioneer) round of translation, called "nuclear marking," and the other for subsequent rounds, called "reverse assembly." The model is designed to accommodate (1) the low abundance of NMD factors, (2) the role of nucleocytoplasmic shuttling proteins in NMD, (3) the independent and nonobligate order of assembly of two different subcomplexes of NMD factors, and (4) the ability of NMD to simultaneously reduce or eliminate the synthesis of truncated proteins produced by nonsense transcripts while down-regulating but not completely eliminating functional proteins produced from error-free NMD-sensitive transcripts.