Messenger RNA regulation: to translate or to degrade

Abstract

Quality control of gene expression operates post-transcriptionally at various levels in eukaryotes. Once transcribed, mRNAs associate with a host of proteins throughout their lifetime. These mRNA-protein complexes (mRNPs) undergo a series of remodeling events that are influenced by and/or influence the translation and mRNA decay machinery. In this review we discuss how a decision to translate or to degrade a cytoplasmic mRNA is reached. Nonsense-mediated mRNA decay (NMD) and microRNA (miRNA)-mediated mRNA silencing are provided as examples. NMD is a surveillance mechanism that detects and eliminates aberrant mRNAs whose expression would result in truncated proteins that are often deleterious to the organism. miRNA-mediated mRNA silencing is a mechanism that ensures a given protein is expressed at a proper level to permit normal cellular function. While NMD and miRNA-mediated mRNA silencing use different decision-making processes to determine the fate of their targets, both are greatly influenced by mRNP dynamics. In addition, both are linked to RNA processing bodies. Possible modes involving 3' untranslated region and its associated factors, which appear to play key roles in both processes, are discussed.

Figure 1

Models for nonsense-mediated decay. (A) The downstream marker posits the presence of a marker protein that is bound to the mRNA downstream of the premature stop codon. The presence of this marker triggers degradation of the PTC containing mRNAs (right panel). In a normal mRNA, the translating ribosomes remove the downstream marker from the coding region of the mRNA, thus preventing normal mRNAs from being targeted to the NMD pathway (left panel). (B) The aberrant termination model posits that termination at a normal stop codon (octagonal stop sign) is different from translation termination at a PTC (aberrant square stop sign). The difference in termination may be due to the proximity of PABP to the normal stop codon (double headed arrow), and/or termination at normal stop codons may be faster than termination at a PTC (clock). These two possibilities are not mutually exclusive. Normal termination at a normal stop codon triggers remodeling into a stable mRNP, whereas aberrant termination at a PTC either prevents this remodeling or triggers remodeling into an aberrant mRNP, which in turn triggers mRNA degradation by a variety of mechanisms. (C) The aberrant termination and downstream marker models can be combined into one coherent model. In this model, the difference between normal termination and aberrant termination can be influenced by a number of different signals. For example, proximity to PABP and other features make termination more normal, whereas downstream markers and other features make termination more aberrant. A preponderance of positive signals causes normal termination, which triggers remodeling into a stable mRNP. A preponderance of negative signals either prevents this remodeling, or triggers remodeling into an aberrant mRNP.

Figure 2

Mechanisms of miRNA-mediated mRNA silencing. After incorporation into the RISC to form miRNPs, miRNAs guide the miRNPs to their target mRNAs by forming imperfect hybrids with 3′UTR sequences of target mRNAs. The interaction between a miRNP and its target mRNA can promote direct inhibition of translation initiation. Alternatively, the miRNP may accelerate deadenylation of the target mRNA, which in turn represses translation initiation or results in mRNA degradation. In P-bodies, miRNA-targeted mRNAs may be sequestered from the translational machinery and degraded or stored for subsequent use.