Computational Modeling and Experimental Analysis of Nonsense-Mediated Decay in Yeast

Abstract

A conserved mRNA surveillance system, referred to as nonsense-mediated decay (NMD), exists in eukaryotic cells to degrade mRNAs containing nonsense codons. This process is important in checking that mRNAs have been properly synthesized and functions, at least in part, to increase the fidelity of gene expression by degrading aberrant mRNAs that, if translated, would produce truncated proteins. Using computational modeling and experimental analysis, we define the alterations in mRNA turnover triggered by NMD in yeast. We demonstrate that the nonsense-containing transcripts are efficiently recognized, targeted for deadenylation-independent decapping, and show NMD triggered accelerated deadenylation regardless of the position of the nonsense codon. We also show that 5′ nonsense codons trigger faster rates of decapping than 3′ nonsense codons, thereby providing a mechanistic basis for the polar effect of NMD. Finally, we construct a computational model that accurately describes the process of NMD and serves as an explanatory and predictive tool.