RNA‐binding Proteins: Regulation of mRNA Splicing, Export and Decay

Abstract

Mammalian messenger ribonucleic acid (mRNA)‐binding proteins regulate gene expression at several steps including pre‐mRNA processing, nucleocytoplasmic export and degradation.

Keywords: pre‐mRNA processing; mRNA transport; mRNA stability; RNA splicing; RNA‐binding proteins; nonsense‐mediated mRNA decay; exon‐junction complex

Figure 1.

Pre‐mRNA splicing. Mammalian pre‐mRNAs contain a 5′ cap (m7G), a 5′ untranslated region (5′ UTR), coding regions (numbered 1, 2 and 3) interrupted by noncoding regions called introns, a 3′ untranslated region (3′ UTR) and a poly(A) tail. Cap binding protein (CBC) and poly(A)‐binding protein (PABP) interact with the 5′ cap and 3′ poly(A) tail, respectively, where they serve to protect the mRNA from decay. The exons are joined together by a complex splicing process initiated by binding of U1 snRNP (U1) to the 5′ splice site (5′ SS). This is followed by the binding of the branchpoint binding protein (BBP) to the branchpoint, and U2 auxiliary factors U2AF 65 (U2 65) and U2AF 35 (U2 35) to the polypyrimidine tract just upstream of the 3′ splice site (3′ SS). SR proteins (SR) are RNA‐binding proteins that are thought to help recruit these splicing factors to pre‐mRNA. Other molecules involved in RNA splicing described in the text are not shown here. The exon junction complex (EJC) is a multiprotein complex deposited near exon–exon junctions after RNA splicing. It appears to facilitate mRNA export and play a critical role in the NMDRNA surveillance pathway. The positions of the start (AUG) and stop (stop sign) codons are marked.

Figure 2.

Nuclear mRNA export and mRNA decay in the cytoplasm. Nucleocytoplasmic export of mRNA requires its interaction with mRNA‐binding proteins (collectively known as an mRNA–protein complex (mRNP)), which in turn interact with nucleoporins lining the nuclear pore. TAP, a component of the EJC, assists in the movement of mRNP through the nuclear pore. Evidence suggests that the first round of translation ejects the EJC and reorganizes the mRNP in a manner that brings the 5′ and the 3′ ends of the mRNA together to form a circular mRNP complex (this first round of translation is pictured as occurring in the cytoplasm but it may also occur in the nucleus). RNA circularizaton allows for more efficient translation by ribosomes. The poly(A) tail of cytoplasmic mRNAs is degraded by poly(A)‐specific ribonucleases (e.g. PARN) at a rate dependent on intrinsic features of the mRNA and specific RNA‐binding proteins that bind to the 3′ UTR. One class of RNA‐binding proteins that regulate deadenylation is ARE‐binding proteins (AUBPs). AUBPs can also trigger mRNA decay by recruiting the exosome, a multiprotein complex that has multiple 3′–5′ nucleases that degrade the body of RNAs. Decapping enzymes, including those associated with the exosome (e.g. DcpS) degrade the 5′ cap.

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References

Black D (2000) Protein diversity from alternative splicing: a challenge for bioinformatics and post genome biology. Cell 103: 367–370.

Blencowe BJ (2000) Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. Trends in Biochemical Science 25: 106–110.

Chen C‐YA and Shyu A‐B (1995) AU‐rich elements: characterization and importance in mRNA degradation. Trends in Biochemical Science 20: 465–470.

Graveley BR (2000) Sorting out the complexity of SR protein functions. RNA 6: 1197–1211.

Grosset C, Chen C‐YA, Xu N, et al. (2000) A mechanism for translationally coupled mRNA turnover: interaction between the poly(A) tail and a c‐fos RNA coding determinant via a protein complex. Cell 103: 29–40.

Guhaniyogi J and Brewer G (2001) Regulation of mRNA stability in mammalian cells. Gene 265: 11–23.

van Hoof A and Parker R (2002) Messenger RNA degradation: beginning at the end. Current Biology 12: R285–R287.

Kramer A (1996) The structure and function of proteins involved in mammalian pre‐mRNA splicing. Annual Review of Biochemistry 65: 367–409.

Lykke‐Andersen J (2001) mRNA quality control: making the message for life or death. Current Biology 11: R88–R91.

Mendell JT and Dietz HC (2001) When the message goes away: disease‐producing mutations that influence mRNA content and performance. Cell 107: 411–414.

Reed R and Hurt E (2002) A conserved mRNA export machinery coupled to pre‐mRNA splicing. Cell 108: 523–531.

Shyu A‐B and Wilkinson MF (2000) The double lives of shuttling mRNA binding proteins. Cell 102: 135–138.

Tucker M and Parker R (2000) Mechanisms and control of mRNA decapping in Saccharomyces cerevisiae. Annual Review of Biochemistry 69: 571–595.

Wagner EJ and Garcia‐Blanco MA (2001) Polypyrimidine tract binding protein antagonizes exon definition. Molecular and Cellular Biology 21: 3281–3288.

Wilkinson MF and Shyu A‐B (2002) RNA surveillance by nuclear scanning? Nature Cell Biology 6: E144–E147.

Zenklusen D and Stutz F (2001) Nuclear export of mRNA. FEBS Letters 498: 150–156.

Further Reading

Lafontaine DL and Tollervey D (2001) The function and synthesis of ribosomes. Nature Reviews Molecular and Cell Biology 7: 514–520.

Maniatis T and Tasic B (2002) Alternative pre‐mRNA splicing and proteome expansion in metazoans. Nature 418: 236–243.

Nagai K and Mattaj IW (1994) RNA–protein interactions in the splicing snRNPs. In: Nagai K and Mattaj IW (eds.) RNA–Protein Interactions, pp. 150–177. Oxford, UK: IRL Press at Oxford University Press

Sachs AB, Sarnow P and Hentze MW (1997) Starting at the beginning, middle, and end: translation initiation in eukaryotes. Cell 89: 831–838.

Sachs AB and Varani G (2000) Eukaryotic translation initiation: there are (at least) two sides to every story. Nature Structural Biology 5: 356–361.

Orphanides G and Reinberg D (2002) A unified theory of gene expression. Cell 108: 439–451.

Wagner E and Lykke‐Andersen J (2002) mRNA surveil‐ lance: the perfect persist. Journal of Cell Science 115: 3033–3038.

Wilusz CJ, Wang W and Peltz SW (2001) Curbing the nonsense: the activation and regulation of mRNA surveillance. Genes and Development 15: 2781–2785.

Wolin SL and Matera AG (1999) The trials and travels of tRNA. Genes and Development 13: 1–10.

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Gudikote, Jayanthi P, and Wilkinson, Miles F(Jan 2006) RNA‐binding Proteins: Regulation of mRNA Splicing, Export and Decay. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005982]