INTERRELATIONSHIPS OF THE PATHWAYS OF mRNA DECAY AND TRANSLATION IN EUKARYOTIC CELLS

Abstract

While the potential importance of mRNA stability to the regulation of gene expression has been recognized, the structures and mechanisms involved in the determination of individual mRNA decay rates have just begun to be elucidated, particularly in mammalian systems and yeast. It is now well established that mRNA decay is not a default process, in which an array of nonspecific nucleases degrades indiscriminately based on target size or ribosome protection of the substrate. Rather, like transcription, RNA processing, and translation, mRNA decay is a precise process dependent on a variety of specific cis-acting sequences and trans-acting factors. Entry into the pathways of mRNA decay is triggered by at least three types of initiating event: poly(A) shortening, arrest of translation at a premature nonsense codon, and endonucleolytic cleavage. Steps subsequent to pol y(A) shortening or premature translational termination converge in a pathway that progresses from removal of the 5′ cap to exonucleolytic digestion of the body of the mRNA. mRNA fragments generated by endonucleolytic cleavage are most likely removed by exonucleolytic decay as well, but these events have not been characterized in detail. Nucleases and other factors (including mRNA sequence elements and autoregulatory proteins) required for the promotion or inhibition of these pathways have been identified by both biochemical and genetic methods and systematic attempts to understand their respective roles have begun. mRNA sequences whose presence or absence has marked effects on mRNA decay rates include the ubiquitous cap and poly(A) tail, sequences that comprise endonuclease cleavage sites, and sequences that promote poly(A) shortening. The latter are found in the 3′-UTR (untranslated region) and in coding regions. Evidence that poly(A) stimulates translation initiation, that some destabilization sequences must be translated in order to function, and that premature translation termination promotes rapid mRNA decay indicates a close linkage between the elements regulating mRNA decay and components of the protein synthesis apparatus. This linkage, and other data, leads us to propose a model for a functional mRNP. In this model, interactions between factors associated with opposite ends of an mRNA stimulate translation initiation and minimize the rate of entry into the pathways of mRNA decay. Events that initiate mRNA decay are postulated to be those that can disrupt this functional complex and create substrates for exonucleolytic digestion.