Killing the messenger: new insights into nonsense-mediated mRNA decay.

many quality control mechanisms developed by cells to maintain the metabolic status quo. The cell’s objective in this case is to destroy mRNA species that contain premature termination codons (PTCs) so that only full-length proteins are produced. Targeted destruction of proteins that misfold as a result of missense mutations (those that result in substitution for amino acids in the protein) and NMD are ancient and evolutionarily conserved strategies to protect the cell from mutations (or errors in transcription) that could yield truncated, potentially hazardous proteins. Eukaryotes as diverse as yeast, Caenorhabditis elegans, and humans employ a limited and overlapping array of proteins that cooperate to destroy mRNA species harboring PTCs. The site of mRNA destruction and the mechanisms by which the cell recognizes premature, as opposed to the constitutive, termination codons have been the objects of intense scrutiny and continuing debate over the last decade and a half. In that time, seven C. elegans genes have been identified that are essential for NMD (named smg-1 through smg-7). Three of these have yeast homologs and the same three genes have human homologs, although the human repertoire is larger than that in yeast (Table 1) as a result of gene duplication. Some additional genes have been identified in yeast as involved in the NMD pathway, but their homologs in mammalian cells and C. elegans have not been extensively explored (see Table 1).