MicroRNAs: New players in an old game

Abstract

One of the cardinal steps in regulating gene expression is mRNA decay, and the numerous pathways and mechanisms that exist to regulate it underscore its importance. mRNA decay is regulated by trans-acting factors that assemble on cis-acting elements (1, 2). Together, they serve to up- or down-regulate a given mRNA. Some of the mechanisms that regulate mRNA levels involve surveillance pathways such as nonsense-mediated decay (NMD) and nonstop decay (NSD). The NMD pathway limits accumulation of mRNAs that contain a premature termination codon and whose translation would produce a truncated protein. In NSD, mRNAs that do not contain a termination codon because of improper poly(A) site selection within the coding region are rapidly degraded by the exosome, a complex of 3′→5′ exoribonucleases (3). Other pathways involve recognition of 3′ UTR sequences by specific RNA-binding proteins. For example, in AU-rich element (ARE)-mediated mRNA decay (AMD), binding of specific ARE recognition proteins to the 3′ UTR initiates mRNA degradation (1, 4). To one degree or another, all these decay pathways involve the step-wise deconstruction of a mRNA involving 3′→5′ trimming of the poly(A) tail, a process referred to as deadenylation; this is followed by removal of the 5′ m7GpppG cap and both 5′→3′ and 3′→5′ degradation of the mRNA body (5–7). This step-wise mechanism, first elucidated in Saccharomyces cerevisiae, has been recognized for some time now. Another mRNA decay pathway that has garnered much attention lately is RNA interference (RNAi). First discovered in Caenorhabditis elegans (8), RNAi has now been observed in several other multicellular organisms, including mammals. RNAi is triggered either by a small interfering RNA (siRNA) or, in some cases, by a microRNA (miRNA) that induces mRNA degradation via endoribonucleolytic cleavage within the site of si/miRNA–mRNA annealing. siRNAs derive from sources such as double-stranded RNA, transposons, and viruses and are perfectly complementary to their mRNA targets (9–11). miRNAs are ≈22 nt in length and are encoded within the genomes of both plants and animals. miRNAs contain regions possessing imperfect complementarity to 3′ UTRs of mRNA subsets to which they anneal. This leads to translational silencing to posttranscriptionally control gene expression (12). In this issue of PNAS, Wu et al. (13) demonstrate that a miRNA can also promote rapid mRNA degradation by accelerating the initial rate-limiting step, deadenylation.