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Review
. 2015:84:325-54.
doi: 10.1146/annurev-biochem-080111-092106. Epub 2015 Mar 11.

The Clothes Make the mRNA: Past and Present Trends in mRNP Fashion

Guramrit Singh  1 , Gabriel Pratt, Gene W Yeo, Melissa J Moore
Affiliations
Review

The Clothes Make the mRNA: Past and Present Trends in mRNP Fashion

Guramrit Singh et al. Annu Rev Biochem. 2015.

Abstract

Throughout their lifetimes, messenger RNAs (mRNAs) associate with proteins to form ribonucleoproteins (mRNPs). Since the discovery of the first mRNP component more than 40 years ago, what is known as the mRNA interactome now comprises >1,000 proteins. These proteins bind mRNAs in myriad ways with varying affinities and stoichiometries, with many assembling onto nascent RNAs in a highly ordered process during transcription and precursor mRNA (pre-mRNA) processing. The nonrandom distribution of major mRNP proteins observed in transcriptome-wide studies leads us to propose that mRNPs are organized into three major domains loosely corresponding to 5' untranslated regions (UTRs), open reading frames, and 3' UTRs. Moving from the nucleus to the cytoplasm, mRNPs undergo extensive remodeling as they are first acted upon by the nuclear pore complex and then by the ribosome. When not being actively translated, cytoplasmic mRNPs can assemble into large multi-mRNP assemblies or be permanently disassembled and degraded. In this review, we aim to give the reader a thorough understanding of past and current eukaryotic mRNP research.

Keywords: RNA granules; RNA processing; RNP remodeling; coupling; mRNP packaging; ribonucleoproteins.

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Figures

Figure 1
Figure 1
Identification and relative abundance of mRNP components. (a) Oligo-dT-cellulose-selected nuclear hnRNP or cytoplasmic mRNP proteins from [3H]-uridine pulse-labeled HeLa cells. (Lanes 1–3) hnRNP proteins recovered from the unbound fraction (lane 1) or from elution with 25% formamide (lane 2) or with 50% formamide (lane 3). (Lanes 4–5) mRNP proteins in the unbound fraction (lane 4) (mainly ribosomal subunits) or eluted with 50% formamide (lane 5). Panel adapted with permission from plate I in Reference 3. (b) Proteins from oligo-dT-cellulose-selected polyribosomal RNPs from human KB cells labeled with [35S]-methionine without (lane 1) or with (lane 2) short-wave UV irradiation. Oligo-dT-selected proteins are as in lane 2, except the radioactive signal was transferred from [3H]-adenosine- and [3H]-uridine-labeled RNAs after UV cross-linking. Panel modified with permission from Reference 10. (c) [35S]-labeled HeLa hnRNP particle proteins coimmunopurified with 4F4 monoclonal antibody (anti–hnRNP C) and resolved by two-dimensional electrophoresis. Panel modified under a Creative Commons license from Reference 14. (d) Copy numbers of mRNA interactome proteins in HeLa cells. HeLa cell copy number data are from Reference 21, and mRNA interactome data are from Reference 49. The interactome proteins are grouped into categories as shown below the x axis. Some proteins that are absent from the HeLa interactome (red dots) are included for better representation within a category. Shown under each protein category are the estimated copy numbers of its members within an mRNP assembled on an average human mRNA with eight exons and seven introns. EJC copy number is based on ~80% EJC occupancy on human mRNAs (35, 36). The SR protein copy number is based on stoichiometric amounts of SR and SR-like proteins associated with the EJC (36). The number of PABP molecules per mRNA is based on a single PABP occupying ~27 adenosines (144) on an average polyA tail of ×250 nt. Abbreviations: EJC, exon junction complex; hnRNP, heterogeneous nuclear ribonucleoprotein; mRNA, messenger RNA; mRNP, mRNA-containing RNP; PABP, polyadenosine (polyA)-binding protein.
Figure 2
Figure 2
Cotranscriptional assembly and compaction of mRNPs. (a) Early steps in cotranscriptional mRNA processing and mRNP assembly. Nascent RNA is represented by blue lines (exons, thick lines; introns, thin lines). Indicated are sequential coupling events mediated by Pol II CTD (brown arrows), coupling events promoted by CBC (black arrows), and interaction between EJC and TREX that may compact the nascent mRNP (thick green dashed line). Individual components are as shown on the right. (b) EJC interactions with self, SR proteins, or TREX complexes that drive nascent mRNP compaction are indicated by thick green dashed lines. Continued sequential coupling action of Pol II CTD is also depicted as in panel a. All individual components are as in the legend on the right. (c) EJC interactions that drive compaction of internal exon mRNPs are now shown as light green spheres that represent several EJC-interacting proteins. The cotranscriptional assembly of 3′-UTR RNP is also shown. Abbreviations: CBC, cap-binding complex; CTD; C-terminal domain; EJC, exon junction complex; mRNP, messenger RNA–containing ribonucleoprotein; Pol II, RNA polymerase II; RNP, ribonucleoprotein; UTR, untranslated region.
Figure 3
Figure 3
Major domains of spliced mammalian mRNPs. (a) Heat map showing percent of binding sites for given RBPs in the 5′ UTR, CDS, or 3′ UTR. The lightest shade indicates no binding, and the darkest shade indicates 100% binding in a given region. Abbreviations: CDS, coding sequence; mRNP, mRNA-containing ribonucleoprotein; UTR, untranslated region. (b) Schematic of the major hypothetical domains of spliced mRNPs: RNA (blue line), internal exon interactome (green sphere), and the 3′-UTR interactome (light blue sphere). Other shapes are as in Figure 2.
Figure 4
Figure 4
Mechanisms of mRNP remodeling in the cytoplasm. (a) mRNP remodeling during mRNA export that is catalyzed by Dbp5 at the cytoplasmic face of the NPC. Molecules represented by each individual shape are either labeled or are as in Figure 2. (b) Active mechanism of nuclear CBC exchange with the cytoplasmic cap-binding protein eIF4E. (c) Phosphorylation (P) and mRNA release of SR proteins mediated by the SRPKs. (d) EJC disassembly during translation by the ribosome-bound PYM protein. Abbreviations: CBC, cap-binding complex; EJC, exon junction complex; mRNA, messenger RNA; mRNP, mRNA-containing ribonucleoprotein; NPC, nuclear pore complex; PABP, polyadenosine (polyA)-binding protein; SRPK, SR-specific protein kinase.
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