Open Access Open Access  Restricted Access Subscription or Fee Access

23 Nonsense-mediated mRNA Decay: From Yeast to Metazoans

Allan Jacobson, Elisa Izaurralde


Mutations resulting in the loss of production of specific proteins are among the major causes of inherited diseases. When defective, any of several steps in the gene expression pathway can be the underlying cause of such diseases (Kazazian 1990), but one of the more common types of mutation that inactivates gene function does so by promoting premature translational termination. Nonsense mutations result in the occurrence of UAA, UAG, or UGA codons in the protein-coding region of an mRNA template, leading to the termination of polypeptide elongation and, generally, to the triggering of a cellular surveillance mechanism dubbed nonsense-mediated mRNA decay, or NMD. The NMD pathway is operative in all eukaryotic cells and ensures that nonsense-containing mRNAs do not accumulate as substrates for the translation apparatus. In turn, the elimination of these transcripts prevents the accumulation of potentially toxic polypeptide fragments.

NMD has been extensively studied in yeast, worms, flies, and mammals, leading to the identification of a key set of regulatory factors and to the elaboration of models explaining the role of these factors in the discrimination of normal versus premature termination and in the promotion of rapid mRNA decay. These studies have provided insight into cellular quality control mechanisms, elucidated fundamental interrelationships between the pathways of mRNA translation and mRNA decay, and set the stage for a potentially major advance in the treatment of a subset of all genetic disorders.

Unlike initiation and elongation, which involve scores of factors, the events that take place...

Full Text: