Eukaryotic mRNAs Exist in the Form of mRNPs from Their Birth to Their Death

KEY CONCEPTS
- mRNA associates with a changing population of proteins during its nuclear maturation and cytoplasmic life.
- Some nuclear-acquired mRNP proteins have roles in the cytoplasm.
- A very large number of RNA-binding proteins exist, most of which remain uncharacterized.
- Different mRNAs are associated with distinct, but overlapping, sets of regulatory proteins, creating RNA regulons.
From the time pre-mRNAs are transcribed in the nucleus until their cytoplasmic destruction, eukaryotic mRNAs are associated with a changing repertoire of proteins. RNA–protein complexes are called ribonucleoprotein particles (RNPs). Many of the pre-mRNA–binding proteins are involved in splicing and processing reactions , and others are involved in quality control . The nuclear maturation of an mRNA comprises multiple remodeling steps involving both the RNA sequence and its complement of proteins. The mature mRNA product is export competent only when fully processed and associated with the correct protein complexes, including TREX (for transcription export), which mediates its association with the nuclear pore export receptor. Mature mRNAs retain multiple binding sites (cis-elements) for different regulatory proteins, most often within their 5′ or 3′ UTRs.
Many nuclear proteins are shed before or during mRNA export to the cytoplasm, whereas others accompany the mRNA and have cytoplasmic roles. For example, once in the cytoplasm the nuclear cap-binding complex participates in the new mRNA’s first translation event, the so-called pioneering round of translation. This first translation initiation is critical for a new mRNA; if it is found to be a defective template it will be rapidly destroyed by a surveillance system (see the section in this chapter titled Quality Control of mRNA Translation Is Performed by Cytoplasmic Surveillance Systems). An mRNA that passes its translation test will spend the rest of its existence associated with a variety of proteins that control its translation, its stability, and sometimes its cellular location. The “nuclear history” of an mRNA is critical in determining its fate in the cytoplasm.
A large number of different RNA-binding proteins (RBPs) are known, and many more are predicted based on genome analysis. The Saccharomyces cerevisiae genome encodes nearly 600 different proteins predicted to bind to RNA, about one-tenth of the total gene number for this organism. Based on similar proportions, the human genome would be expected to contain more than 2,000 such proteins. These estimates are based on the presence of characterized RNA-binding domains, and it is likely that additional RNA-binding domains remain to be found. The RNA targets and functions of the great majority of these RBPs are unknown, although it is considered likely that a large fraction of them interact with pre-mRNA or mRNA. This kind of analysis does not include the many proteins that do not bind RNA directly, but participate in RNAbinding complexes.
An important insight into why the number of different mRNA-binding proteins is so large has come from the finding that mRNAs are associated with distinct, but overlapping, sets of RBPs. Studies that have matched specific RBPs with their target mRNAs have revealed that those mRNAs encode proteins with shared features such as involvement in similar cellular processes or location. Thus, the repertoire of bound proteins catalogues the mRNA. For example, hundreds of yeast mRNAs are bound by one or more of six related Puf proteins. Puf1 and Puf2 bind mostly mRNAs encoding membrane proteins, whereas Puf3 binds mostly mRNAs encoding mitochondrial proteins, and so on. A current model, illustrated in FIGURE 1, proposes that the coordinate control of posttranscriptional processes of mRNAs is mediated by the combinatorial action of multiple RBPs, much like the coordinate control of gene transcription is mediated by the right combinations of transcription factors . The set of mRNAs that share a particular type of RBP is called an RNA regulon.

FIGURE 1.The concept of an RNA regulon. Eukaryotic mRNAs are bound by a variety of proteins that control their translation, localization, and stability. The subset of mRNAs that have a binding protein in common are considered part of the same regulon. In the diagram, mRNAs a and d are part of regulon 1; mRNAs a, c, and e are part of regulon 2; and so on.