In nonsense-mediated decay, the first step is removal of the cap from the mRNA. (This contrasts with normal mRNA degradation where the poly (A) tail must be removed before the cap—see above). Next, the mRNA is degraded from the exposed 5'-end.

In yeast, less than 5% of genes contain introns. Therefore most yeast genes do not require splicing of the primary transcript to generate the mRNA. Consequently there are no exon-exon junctions to serve as markers for nonsense-mediated decay. Instead, most yeast mRNA contains downstream sequence elements (DSE). The DSE sequences are rather ill-defined but are AU rich. The DSE sequences serve as binding sites for the proteins involved as markers in nonsense-mediated decay.

Nonsense-mediated decay in yeast also differs from animals in another respect. In both mammals and in the roundworm, Caenorhabditis elegans, NMD is regulated by phosphorylation of protein Upf1. This does not occur in yeast. Phosphorylation probably occurs during the translation termination process and is necessary for NMD to proceed. Addition and removal of phosphate from Upf1 requires several other proteins. These are absent in yeast.

Yeast mutants with knockouts in the Upf genes grow nearly normally on many media, but show impairment of mitochondrial function. C. elegans with impaired NMD is viable. However, the reproductive system develops abnormally and fertility is greatly reduced. In mammals, defects in the Upf genes appear to be lethal.

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