Regulation of cytoplasmic mRNA decay

Key Points Cytoplasmic mRNA decay constitutes an important post-transcriptional mechanism in mammalian cells that, together with gene transcription, precursor mRNA (pre-mRNA) processing and mRNA transport mechanisms, regulates the ultimate level of protein-encoding gene expression. The regulation of cytoplasmic mRNA half-life is mediated by mRNA-binding proteins and non-coding RNAs (ncRNAs), such as microRNAs and long non-coding RNAs. The level and/or activity of mRNA-binding proteins can vary depending on their post-translational modifications, which can differ between different cell types or changes in cell signalling within a particular cell type; the level and/or activity of ncRNAs can be regulated by the efficiency of their formation. The regulation of cytoplasmic mRNA half-life can also be affected by the translational status of the mRNA. Translation can remove regulatory proteins or ncRNAs from mRNAs should they associate with mRNA coding regions. Some mechanisms of mRNA decay largely maintain the quality of gene expression, as exemplified by nonsense-mediated mRNA decay (NMD). NMD generally degrades newly synthesized mRNAs, depending on where translation terminates, and it is regulated as a means of maintaining cellular homeostasis. Genes encoding protein products that contribute to a distinct phase (or phases) of the cell cycle are often regulated at the level of mRNA half-life as well as the level of transcription. An example of this is provided by metazoan histone genes, whose mRNAs that are degraded at the end of S phase when DNA synthesis is completed and there is no further need for histone protein synthesis. mRNA decay is a target of numerous signal transduction pathways. Site-specific phosphorylation controls the subcellular distribution of stabilizing and destabilizing proteins and their ability to interact with degradative enzymes to activate decay. Nuclear receptors can have a dual function in activating decay, by inducing the expression of one or more destabilizing proteins or by binding directly to mRNAs to activate their degradation. The AU-rich elements (AREs) are the largest group of cis -acting elements controlling mRNA decay. Destabilizing ARE-binding proteins function primarily by recruiting enzymes that catalyse shortening of the poly(A) tail, and ARE-containing mRNAs are stabilized by modifications (for example, by phosphorylation) that block the recruitment of deadenylases or by competitive binding of stabilizing ARE-binding p