30 Nonsense-mediated RNA Decay in Mammalian Cells: A Splicing-dependent Means to Down-regulate the Levels of mRNAs That Prematurely Terminate Translation

Abstract

Within all eukaryotic organisms that have been examined, including yeast, worms, flies, and mammals, there is a surveillance mechanism referred to as nonsense-mediated RNA decay (NMD). NMD provides a means to down-regulate aberrant gene expression by degrading RNAs harboring premature termination codons (PTCs). NMD also contributes, both directly and indirectly, to a proper balance of normal gene expression by degrading specific, naturally occurring transcripts. In this chapter, I describe the effects of PTCs on RNA metabolism in mammalian cells with the aim of presenting current mechanistic concepts and progress toward using PTC suppression as a treatment for human genetic diseases. Related studies of NMD in yeast are discussed in Chapter 29.

REASONS FOR NMD
PTCs (UGA, UAA, and UAG) can arise as a consequence of routine cellular processes that are occasionally programmed but are usually caused by errors. Errors permit molecular diversity, cellular adaptability, and improved organismal viability, but they do so at the cost of leading to nonproductive or deleterious gene expression most of the time. Processes by which the generation of PTCs is programmed include the posttranscriptional cytidine deamination of nuclear apolipoprotein (apo) B transcripts in enterocytes of the mammalian small intestine that results in conversion of codon 2153 within exon 26 from CAA to UAA (for review, see Chang et al. 1998). Processes by which PTCs arise as the consequence of errors include incomplete or inaccurate pre-mRNA splicing, which has the potential to generate multiple proteins from a single gene but more often generates either an intron-derived...