Before proceeding, let’s quickly review the steps in gene expression at which control is exerted. We saw in Chapter 9 that regulation of transcription initiation and transcription elongation in the promoter-proximal region are the initial mechanisms for controlling the expression of genes in the DNA → RNA → protein pathway. In the preceding sections of this chapter, we learned that the expression of protein isoforms is controlled by the regulation of alternative RNA splicing and of cleavage and polyadenylation at alternative poly(A) sites. Although nuclear export of fully and correctly processed mRNPs to the cytoplasm is rarely regulated, the export of improperly processed or aberrantly remodeled pre-mRNPs is prevented, and such abnormal transcripts are degraded by exosomes. However, retroviruses, including HIV, have evolved mechanisms that permit pre-mRNAs that retain splice sites to be exported and translated.

In this section, we consider other mechanisms of post-transcriptional control that contribute to regulating the expression of many genes. Most of these mechanisms operate in the cytoplasm, controlling the stability or localization of mRNA or its translation into protein. The concentration of an mRNA in the cytoplasm is determined by its rate of synthesis and its rate of degradation. The most stable mRNAs, which encode proteins required in large amounts (such as the ribosomal proteins), can accumulate to very high copy numbers per cell. In contrast, highly unstable mRNAs, which encode proteins expressed in short bursts (such as cytokines, secreted proteins that regulate the immune response), rarely achieve such high concentrations even when transcribed, processed, and exported from the nucleus at high rates. We begin by discussing the major pathways that degrade mRNAs.

Next we discuss two related mechanisms of gene control that provide powerful new techniques for manipulating the expression of specific genes for experimental and therapeutic purposes. These mechanisms are controlled by short (~22-nucleotide) single-stranded RNAs called micro-RNAs (miRNAs) and short interfering RNAs (siRNAs). Both base-pair with specific target mRNAs, causing their rapid degradation (siRNAs) or inhibiting their translation and inducing a slower form of degradation (miRNAs). Many miRNAs can target more than one mRNA. Consequently, these mechanisms contribute significantly to the regulation of gene expression. Short interfering RNAs, involved in a process called RNA interference, are an important cellular defense against viral infection and excessive transposition by retrotransposons. We also discuss mechanisms that control the overall rate of protein synthesis, as well as highly specific mechanisms that regulate the translation and stability of particular mRNAs. Finally, we discuss mechanisms that control the localization of mRNAs in the cytoplasm of asymmetric cells so that the encoded protein is translated at sites in the cell where it is needed.