ABSTRACT
N onsense-mediated mRNA decay (NMD) is ubiquitous among eukaryotes. While this degree o f conservation certainly attests to strong evolutionary pressure for maintenance of NM D, the mechanistic basis for this maintenance has remained both speculative and controversial. The fact that NM D was initially discovered, and has been most comprehensively studied, in the context of acquired premature termination codons (PTCs) that disrupt protein coding potential and exert overt phenotypic consequences (including dis ease), has certainly flavored (if not biased) interpretation of its basic physiologic purpose(s). The prevailing view has been that NM D protects the organism from deleterious truncated peptides with dominant-negative or gain-of-function potential that would be expressed from nonsense alleles if the corresponding transcripts were stable. Given that the fitness of indi vidual organisms, as opposed to the population at large, is of litde consequence to evolution, this restricted function of NM D cannot plausibly explain its conservation. This chapter will oudine the emerging view that NM D plays a broad role in the regulation of gene expression, and, as a direct or indirect consequence, in the maintenance of critical developmental and homeostatic functions including orchestration of the response to environmental stress. The biologic and medical implications of this insight will also be discussed.
