Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Messenger-RNA-binding proteins and the messages they carry

Nature Reviews Molecular Cell Biology volume 3, pages 195–205 (2002)Cite this article

Key Points

  • Eukaryotic messenger RNAs require information that specifies their nuclear export, subcellular localization, translation and stability, in order to function properly.

  • It is becoming apparent that this information is provided not only by the mRNA sequence, but also by specific RNA-binding proteins - collectively referred to as heterogeneous nuclear ribonucleoproteins (hnRNP proteins) or mRNA-protein complex proteins (mRNP proteins).

  • Most of the hnRNP proteins associate with the pre-mRNAs co-transcriptionally, whereas others associate later as a consequence of the processing reactions that form the mRNAs. Many hnRNP proteins are removed with the excision of introns during splicing, and the spliceosome clears away proteins from the vicinity of exon-exon junctions, leaving the exon-exon junction complex (EJC) in its wake. However, many of the hnRNP proteins remain on the mRNAs after splicing and, together with the EJC proteins, accompany the mRNAs to the cytoplasm.

  • The specific constellation of proteins on a given mRNA carries an impression of its childhood experiences and profoundly influences its fate. What results is an mRNP that is much richer in information than the sequence of the mRNA itself. Because several proteins are bound at exon-exon junctions after export to the cytoplasm, they provide a molecular memory that documents the overall structure of the pre-mRNA, and communicates crucial information to the translational machinery for the surveillance of nonsense mutations and for mRNA localization and translation.

Abstract

From sites of transcription in the nucleus to the outreaches of the cytoplasm, messenger RNAs are associated with RNA-binding proteins. These proteins influence pre-mRNA processing as well as the transport, localization, translation and stability of mRNAs. Recent discoveries have shown that one group of these proteins marks exon?exon junctions and has a role in mRNA export. These proteins communicate crucial information to the translation machinery for the surveillance of nonsense mutations and for mRNA localization and translation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: HnRNP proteins and mRNP proteins along the pathway of mRNA biogenesis.
Figure 2: Model for the functional coupling of pre-mRNA splicing and nonsense-mediated decay.
Figure 3: Model for the role of the exon?exon junction on nonsense-mediated mRNA decay.

Similar content being viewed by others

References

  1. Dreyfuss, G., Matunis, M. J., Pinol-Roma, S. & Burd, C. G. hnRNP proteins and the biogenesis of mRNA. Annu. Rev. Biochem. 62, 289?321 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Krecic, A. M. & Swanson, M. S. hnRNP complexes: composition, structure, and function. Curr. Opin. Cell Biol. 11, 363?371 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Shyu, A. B. & Wilkinson, M. F. The double lives of shuttling mRNA binding proteins. Cell 102, 135?138 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Kamma, H., Portman, D. S. & Dreyfuss, G. Cell type-specific expression of hnRNP proteins. Exp. Cell Res. 221, 187?196 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Hanamura, A., Caceres, J. F., Mayeda, A., Franza, B. R. Jr & Krainer, A. R. Regulated tissue-specific expression of antagonistic pre-mRNA splicing factors. RNA 4, 430?444 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Markovtsov, V. et al. Cooperative assembly of an hnRNP complex induced by a tissue-specific homolog of polypyrimidine tract binding protein. Mol. Cell. Biol. 20, 7463?7479 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pinol-Roma, S., Swanson, M. S., Gall, J. G. & Dreyfuss, G. A novel heterogeneous nuclear RNP protein with a unique distribution on nascent transcripts. J. Cell Biol. 109, 2575?2587 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Van der Houven van Oordt, W. et al. The MKK(3/6)?p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. J. Cell Biol. 149, 307?316 (2000).This study shows that the MKK(3/6)?p38 pathway can mediate the cytoplasmic accumulation of hnRNP A1, and indicates that signal transduction mechanisms can regulate pre-mRNA splicing in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mandal, M. et al. Growth factors regulate heterogeneous nuclear ribonucleoprotein K expression and function. J. Biol. Chem. 276, 9699?9704 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Habelhah, H. et al. ERK phosphorylation drives cytoplasmic accumulation of hnRNP-K and inhibition of mRNA translation. Nature Cell Biol. 3, 325?330 (2001).This study shows that hnRNP K is phosphorylated by mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) both in vitro and in vivo . This phosphorylation leads to the cytoplasmic localization of hnRNP K, which is required for its ability to silence mRNA translation. These findings indicate a role for hnRNP proteins in signal-transduction pathways.

    Article  CAS  PubMed  Google Scholar 

  11. Burd, C. G. & Dreyfuss, G. Conserved structures and diversity of functions of RNA-binding proteins. Science 265, 615?621 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Siomi, H. & Dreyfuss, G. A nuclear localization domain in the hnRNP A1 protein. J. Cell Biol. 129, 551?560 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Michael, W. M., Choi, M. & Dreyfuss, G. A nuclear export signal in hnRNP A1: a signal-mediated, temperature-dependent nuclear protein export pathway. Cell 83, 415?422 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Weighardt, F., Biamonti, G. & Riva, S. Nucleo-cytoplasmic distribution of human hnRNP proteins: a search for the targeting domains in hnRNP A1. J. Cell Sci. 108, 545?555 (1995).

    CAS  PubMed  Google Scholar 

  15. Tomonaga, T. & Levens, D. Heterogeneous nuclear ribonucleoprotein K is a DNA-binding transactivator. J. Biol. Chem. 270, 4875?4881 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Michelotti, E. F., Michelotti, G. A., Aronsohn, A. I. & Levens, D. Heterogeneous nuclear ribonucleoprotein K is a transcription factor. Mol. Cell. Biol. 16, 2350?2360 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Du, Q., Melnikova, I. N. & Gardner, P. D. Differential effects of heterogeneous nuclear ribonucleoprotein K on Sp1- and Sp3-mediated transcriptional activation of a neuronal nicotinic acetylcholine receptor promoter. J. Biol. Chem. 273, 19877?19883 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Miau, L. H., Chang, C. J., Shen, B. J., Tsai, W. H. & Lee, S. C. Identification of heterogeneous nuclear ribonucleoprotein K (hnRNP K) as a repressor of C/EBPβ-mediated gene activation. J. Biol. Chem. 273, 10784?10791 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Ishikawa, F., Matunis, M. J., Dreyfuss, G. & Cech, T. R. Nuclear proteins that bind the pre-mRNA 3′ splice site sequence r(UUAG/G) and the human telomeric DNA sequence d(TTAGGG)n. Mol. Cell. Biol. 13, 4301?4310 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. La Branche, H. et al. Telomere elongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase. Nature Genet. 19, 199?202 (1998).

    Article  CAS  Google Scholar 

  21. Eversole, A. & Maizels, N. In vitro properties of the conserved mammalian protein hnRNP D suggest a role in telomere maintenance. Mol. Cell. Biol. 20, 5425?5432 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fiset, S. & Chabot, B. hnRNP A1 may interact simultaneously with telomeric DNA and the human telomerase RNA in vitro. Nucleic Acids Res. 29, 2268?2275 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dempsey, L. A., Sun, H., Hanakahi, L. A. & Maizels, N. G4 DNA binding by LR1 and its subunits, nucleolin and hnRNP D, A role for G?G pairing in immunoglobulin switch recombination. J. Biol. Chem. 274, 1066?1071 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Mayeda, A. & Krainer, A. R. Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2. Cell 68, 365?375 (1992).This paper reports that the relative concentrations of hnRNP A1 and the essential splicing factor SF2 modulate 5′ splice site selection in vitro.

    Article  CAS  PubMed  Google Scholar 

  25. Caceres, J. F., Stamm, S., Helfman, D. M. & Krainer, A. R. Regulation of alternative splicing in vivo by overexpression of antagonistic splicing factors. Science 265, 1706?1709 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Yang, X. et al. The A1 and A1B proteins of heterogeneous nuclear ribonucleoparticles modulate 5′ splice site selection in vivo. Proc. Natl Acad. Sci. USA 91, 6924?6928 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Min, H., Chan, R. C. & Black, D. L. The generally expressed hnRNP F is involved in a neural-specific pre-mRNA splicing event. Genes Dev. 9, 2659?2671 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Chan, R. C. & Black, D. L. The polypyrimidine tract binding protein binds upstream of neural cell-specific c-src exon N1 to repress the splicing of the intron downstream. Mol. Cell. Biol. 17, 4667?4676 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chabot, B., Blanchette, M., Lapierre, I. & La Branche, H. An intron element modulating 5′ splice site selection in the hnRNP A1 pre-mRNA interacts with hnRNP A1. Mol. Cell. Biol. 17, 1776?1786 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ashiya, M. & Grabowski, P. J. A neuron-specific splicing switch mediated by an array of pre-mRNA repressor sites: evidence of a regulatory role for the polypyrimidine tract binding protein and a brain-specific PTB counterpart. RNA 3, 996?1015 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Chou, M. Y., Rooke, N., Turck, C. W. & Black, D. L. hnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells. Mol. Cell. Biol. 19, 69?77 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Del Gatto-Konczak, F., Olive, M., Gesnel, M. C. & Breathnach, R. hnRNP A1 recruited to an exon in vivo can function as an exon splicing silencer. Mol. Cell. Biol. 19, 251?260 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen, C. D., Kobayashi, R. & Helfman, D. M. Binding of hnRNP H to an exonic splicing silencer is involved in the regulation of alternative splicing of the rat β-tropomyosin gene. Genes Dev. 13, 593?606 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mourelatos, Z., Abel, L., Yong, J., Kataoka, N. & Dreyfuss, G. SMN interacts with a novel family of hnRNP and spliceosomal proteins. EMBO J. 20, 5443?5452 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tange, T. O., Damgaard, C. K., Guth, S., Valcarcel, J. & Kjems, J. The hnRNP A1 protein regulates HIV-1 tat splicing via a novel intron silencer element. EMBO J. 20, 5748?5758 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Russell, I. D. & Tollervey, D. NOP3 is an essential yeast protein which is required for pre-rRNA processing. J. Cell Biol. 119, 737?747 (1992).

    Article  CAS  PubMed  Google Scholar 

  37. Kessler, M. M. et al. Hrp1, a sequence-specific RNA-binding protein that shuttles between the nucleus and the cytoplasm, is required for mRNA 3′ -end formation in yeast. Genes Dev. 11, 2545?2556 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Moreira, A. et al. The upstream sequence element of the C2 complement poly(A) signal activates mRNA 3′ end formation by two distinct mechanisms. Genes Dev. 12, 2522?2534 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Minvielle-Sebastia, L. et al. Control of cleavage site selection during mRNA 3′ end formation by a yeast hnRNP. EMBO J. 17, 7454?7468 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bagga, P. S., Arhin, G. K. & Wilusz, J. DSEF-1 is a member of the hnRNP H family of RNA-binding proteins and stimulates pre-mRNA cleavage and polyadenylation in vitro. Nucleic Acids Res. 26, 5343?5350 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lee, M. S., Henry, M. & Silver, P. A. A protein that shuttles between the nucleus and the cytoplasm is an important mediator of RNA export. Genes Dev. 10, 1233?1246 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Liu, X. & Mertz, J. E. HnRNP L binds a cis-acting RNA sequence element that enables intron-dependent gene expression. Genes Dev. 9, 1766?1780 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Izaurralde, E. et al. A role for the M9 transport signal of hnRNP A1 in mRNA nuclear export. J. Cell Biol. 137, 27?35 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gallouzi, I. E. & Steitz, J. A. Delineation of mRNA export pathways by the use of cell-permeable peptides. Science 294, 1895?1901 (2001).This paper provides evidence that there are many export pathways for specific mRNAs. Cell-permeable peptides fused to nuclear-export signals inhibit interactions between particular receptor and adaptor pairs, and block the corresponding export pathway. This allowed the authors to attribute the export of c-myc mRNA to two independent pathways; one mediated by CRM1, and another by transportin 2.

    Article  CAS  PubMed  Google Scholar 

  45. Hoek, K. S., Kidd, G. J., Carson, J. H. & Smith, R. hnRNP A2 selectively binds the cytoplasmic transport sequence of myelin basic protein mRNA. Biochemistry 37, 7021?7029 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. Matunis, E. L., Kelley, R. & Dreyfuss, G. Essential role for a heterogeneous nuclear ribonucleoprotein (hnRNP) in oogenesis: hrp40 is absent from the germ line in the dorsoventral mutant squid. Proc. Natl Acad. Sci. USA 91, 2781?2784 (1994).

    Article  CAS  PubMed  Google Scholar 

  47. Cote, C. A. et al. A Xenopus protein related to hnRNP I has a role in cytoplasmic RNA localization. Mol. Cell 4, 431?437 (1999).Localization of Vg1 RNA within the Xenopus oocyte is mediated by recognition of a localization element within its 3′ untranslated region. VgRBP60, which is homologous to a human hnRNP I (PTB), is shown to be a specific binder of this sequence and to co-localize with Vg1 RNA.

    Article  CAS  PubMed  Google Scholar 

  48. Mouland, A. J. et al. RNA trafficking signals in human immunodeficiency virus type 1. Mol. Cell. Biol. 21, 2133?2143 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Carson, J. H., Cui, H. & Barbarese, E. The balance of power in RNA trafficking. Curr. Opin. Neurobiol. 11, 558?563 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Ostareck, D. H. et al. mRNA silencing in erythroid differentiation: hnRNP K and hnRNP E1 regulate 15-lipoxygenase translation from the 3′ end. Cell 89, 597?606 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Collier, B., Goobar-Larsson, L., Sokolowski, M. & Schwartz, S. Translational inhibition in vitro of human papillomavirus type 16 L2 mRNA mediated through interaction with heterogenous ribonucleoprotein K and poly(rC)-binding proteins 1 and 2. J. Biol. Chem. 273, 22648?22656 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Silvera, D., Gamarnik, A. V. & Andino, R. The N-terminal K homology domain of the poly(rC)-binding protein is a major determinant for binding to the poliovirus 5′ -untranslated region and acts as an inhibitor of viral translation. J. Biol. Chem. 274, 38163?38170 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Ostareck, D. H., Ostareck-Lederer, A., Shatsky, I. N. & Hentze, M. W. Lipoxygenase mRNA silencing in erythroid differentiation: the 3′ UTR regulatory complex controls 60S ribosomal subunit joining. Cell 104, 281?290 (2001).LOX mRNA translation is controlled by the differentiation control element in the 3′ untranslated region and by hnRNPs K and E1. This paper shows that the crucial step is joining of the 60S subunit to mRNA.

    Article  CAS  PubMed  Google Scholar 

  54. Kiledjian, M., Wang, X. & Liebhaber, S. A. Identification of two KH domain proteins in the α-globin mRNP stability complex. EMBO J. 14, 4357?4364 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kiledjian, M., DeMaria, C. T., Brewer, G. & Novick, K. Identification of AUF1 (heterogeneous nuclear ribonucleoprotein D) as a component of the α-globin mRNA stability complex. Mol. Cell. Biol. 17, 4870?4876 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rajagopalan, L. E., Westmark, C. J., Jarzembowski, J. A. & Malter, J. S. hnRNP C increases amyloid precursor protein (APP) production by stabilizing APP mRNA. Nucleic Acids Res. 26, 3418?3423 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chkheidze, A. N. et al. Assembly of the α-globin mRNA stability complex reflects binary interaction between the pyrimidine-rich 3′ untranslated region determinant and poly(C) binding protein αCP. Mol. Cell. Biol. 19, 4572?4581 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Shih, S. C. & Claffey, K. P. Regulation of human vascular endothelial growth factor mRNA stability in hypoxia by heterogeneous nuclear ribonucleoprotein L. J. Biol. Chem. 274, 1359?1365 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Loflin, P., Chen, C. Y. & Shyu, A. B. Unraveling a cytoplasmic role for hnRNP D in the in vivo mRNA destabilization directed by the AU-rich element. Genes Dev. 13, 1884?1897 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Xu, N., Chen, C. Y. & Shyu, A. B. Versatile role for hnRNP D isoforms in the differential regulation of cytoplasmic mRNA turnover. Mol. Cell. Biol. 21, 6960?6971 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pinol-Roma, S. & Dreyfuss, G. Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm. Nature 355, 730?732 (1992).This paper shows that several of the abundant hnRNP proteins, such as A1, shuttle rapidly and continuously between the nucleus and the cytoplasm. It further shows that these shuttling proteins are also bound to mRNAs in the cytoplasm, and proposes functions for shuttling proteins in mRNA export, mRNA function in the cytoplasm, and nucleo-cytoplasmic signal transduction.

    Article  CAS  PubMed  Google Scholar 

  62. Alzhanova-Ericsson, A. T. et al. A protein of the SR family of splicing factors binds extensively to exonic Balbiani ring pre-mRNA and accompanies the RNA from the gene to the nuclear pore. Genes Dev. 10, 2881?2893 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Caceres, J. F., Screaton, G. R. & Krainer, A. R. A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm. Genes Dev. 12, 55?66 (1998).This paper shows that some, but not all, of the SR proteins shuttle between the nucleus and the cytoplasm.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Burd, C. G., Matunis, E. L. & Dreyfuss, G. The multiple RNA-binding domains of the mRNA poly(A)-binding protein have different RNA-binding activities. Mol. Cell. Biol. 11, 3419?3424 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Imataka, H., Gradi, A. & Sonenberg, N. A newly identified N-terminal amino acid sequence of human eIF4G binds poly(A)-binding protein and functions in poly(A)-dependent translation. EMBO J. 17, 7480?7489 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tarun, S. Z. Jr & Sachs, A. B. A common function for mRNA 5′ and 3′ ends in translation initiation in yeast. Genes Dev. 9, 2997?3007 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Piron, M., Vende, P., Cohen, J. & Poncet, D. Rotavirus RNA-binding protein NSP3 interacts with eIF4GI and evicts the poly(A) binding protein from eIF4F. EMBO J. 17, 5811?5821 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Visa, N. et al. A pre-mRNA-binding protein accompanies the RNA from the gene through the nuclear pores and into polysomes. Cell 84, 253?264 (1996).This study describes how electron microscopy with Balbiani ring pre-mRNA for C. tentans was used to describe hrp36, which is similar to the mammalian hnRNP A1. When hrp36 is added to Balbiani ring RNA during transcription, it stays on the nucleoplasmic Balbiani ring particles, and remains associated with Balbiani ring RNA after export.

    Article  CAS  PubMed  Google Scholar 

  69. Hirose, Y. & Manley, J. L. RNA polymerase II and the integration of nuclear events. Genes Dev. 14, 1415?1429 (2000).

    CAS  PubMed  Google Scholar 

  70. Shatkin, A. J. & Manley, J. L. The ends of the affair: capping and polyadenylation. Nature Struct. Biol. 7, 838?842 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Wu, Z. A., Murphy, C., Callan, H. G. & Gall, J. G. Small nuclear ribonucleoproteins and heterogeneous nuclear ribonucleoproteins in the amphibian germinal vesicle: loops, spheres, and snurposomes. J. Cell Biol. 113, 465?483 (1991).

    Article  CAS  PubMed  Google Scholar 

  72. Daneholt, B. Assembly and transport of a premessenger RNP particle. Proc. Natl Acad. Sci. USA 98, 7012?7017 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Visa, N., Izaurralde, E., Ferreira, J., Daneholt, B. & Mattaj, I. W. A nuclear cap-binding complex binds Balbiani ring pre-mRNA cotranscriptionally and accompanies the ribonucleoprotein particle during nuclear export. J. Cell Biol. 133, 5?14 (1996).

    Article  CAS  PubMed  Google Scholar 

  74. Sun, X. et al. The hrp23 protein in the balbiani ring pre-mRNP particles is released just before or at the binding of the particles to the nuclear pore complex. J. Cell Biol. 142, 1181?1193 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Luo, M. J. & Reed, R. Splicing is required for rapid and efficient mRNA export in metazoans. Proc. Natl Acad. Sci. USA 96, 14937?14942 (1999).The authors show that spliced mRNAs are exported at a higher rate than intronless mRNAs, and that the spliced mRNP complex has a different protein composition from that of the intronless mRNP complex. This indicates the presence of an export-promoting factor(s) that is recruited to the mRNA by the process of splicing.

    Article  CAS  PubMed  Google Scholar 

  76. Le Hir, H., Moore, M. J. & Maquat, L. E. Pre-mRNA splicing alters mRNP composition: evidence for stable association of proteins at exon?exon junctions. Genes Dev. 14, 1098?1108 (2000).The authors use an ultraviolet-induced crosslinking technique for mRNAs that contain a single photoreactive group and 32P at exon?exon junctions. After in vitro splicing and crosslinking, only proteins that are bound to the junction can be labelled. The results show that splicing recruits a new set of proteins near the exon?exon junction.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Blencowe, B. J., Issner, R., Nickerson, J. A. & Sharp, P. A. A coactivator of pre-mRNA splicing. Genes Dev. 12, 996?1009 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kataoka, N. et al. Pre-mRNA splicing imprints mRNA in the nucleus with a novel RNA-binding protein that persists in the cytoplasm. Mol. Cell 6, 673?682 (2000).This study shows that a new RNA-binding protein, Y14, binds preferentially to mRNAs that are produced by splicing both in vitro and in vivo . These results also show that pre-mRNA splicing results in the binding of specific proteins to the mRNAs. Binding of these proteins persists on the same mRNAs after export to the cytoplasm.

    Article  CAS  PubMed  Google Scholar 

  79. Le Hir, H., Izaurralde, E., Maquat, L. E. & Moore, M. J. The spliceosome deposits multiple proteins 20?24 nucleotides upstream of mRNA exon?exon junctions. EMBO J. 19, 6860?6869 (2000).This study identifies the binding site of mRNA-specific proteins (SRm160, DEK, Y14, Aly and RNPS1) on spliced mRNAs near exon?exon junctions, and further characterizes the multi-protein complex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kim, V. N. et al. The Y14 protein communicates to the cytoplasm the position of exon?exon junctions. EMBO J. 20, 2062?2068 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mayeda, A. et al. Purification and characterization of human RNPS1: a general activator of pre-mRNA splicing. EMBO J. 18, 4560?4570 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Stutz, F. et al. REF, an evolutionarily conserved family of hnRNP-like proteins, interacts with TAP/Mex67p and participates in mRNA nuclear export. RNA 6, 638?650 (2000).The authors show that Mex67 directly interacts with Yra1, and that this interaction is evolutionarily conserved, as Yra1 can also interact with TAP, the mammalian homologue of Mex67. Using database searches with Yra1, it turned out that Yra1 belongs to an evolutionarily conserved family of hnRNP-like proteins across several species. These proteins were named REF-bps, as they bind to both RNA and export factors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kataoka, N., Diem, M. D., Kim, V. N., Yong, J. & Dreyfuss, G. Magoh, a human homolog of Drosophila mago nashi protein, is a component of the splicing-dependent exon?exon junction complex. EMBO J. 20, 6424?6433 (2001).This paper shows that a human homologue of Drosophila mago nashi protein is a new component of the exon?exon junction complex, and that it binds specifically to Y14. It further shows that magoh and Y14 bind the mRNA-export factor TAP.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Le Hir, H., Gatfield, D., Braun, I. C., Forler, D. & Izaurralde, E. The protein Mago provides a link between splicing and mRNA localization. EMBO Rep. 2, 1119?1124 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kim, V. N., Kataoka, N. & Dreyfuss, G. Role of the nonsense-mediated decay factor hUpf3 in the splicing-dependent exon?exon junction complex. Science 293, 1832?1836 (2001).This study shows that Upf3 is a bona fide component of the exon?exon junction complex, and provides a probable molecular link between splicing and an effector of nonsense-mediated mRNA decay.

    Article  CAS  PubMed  Google Scholar 

  86. Le Hir, H., Gatfield, D., Izaurralde, E. & Moore, M. J. The exon?exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. EMBO J. 20, 4987?4997 (2001).This shows that both mRNA export factors (TAP and p15) and nonsense-mediated mRNA decay factors (Upf2 and 3) are enriched near exon?exon junctions, which indicates that the exon?exon junction complex might function in both pathways.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. McGarvey, T. et al. The acute myeloid leukemia-associated protein, DEK, forms a splicing-dependent interaction with exon-product complexes. J. Cell Biol. 150, 309?320 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhou, Z. et al. The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 407, 401?405 (2000).This study reports direct evidence for a function for Aly/REF in mRNA export based on oocyte-injection studies. Now it seems, however, that Aly/REF might not be the only component of the exon?exon junction complex that has this activity, and also that Aly/REF might also facilitate the export of intronless mRNAs.

    Article  CAS  PubMed  Google Scholar 

  89. Rodrigues, J. P. et al. REF proteins mediate the export of spliced and unspliced mRNAs from the nucleus. Proc. Natl Acad. Sci. USA 98, 1030?1035 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Lykke-Andersen, J., Shu, M. D. & Steitz, J. A. Communication of the position of exon?exon junctions to the mRNA surveillance machinery by the protein RNPS1. Science 293, 1836?1839 (2001).RNPS1 and, to a lesser extent, Y14 are found to have a role in nonsense-mediated mRNA decay, presumably through their interactions with Upf3.

    Article  CAS  PubMed  Google Scholar 

  91. Mohr, S. E., Dillon, S. T. & Boswell, R. E. The RNA-binding protein Tsunagi interacts with Mago Nashi to establish polarity and localize oskar mRNA during Drosophila oogenesis. Genes Dev. 15, 2886?2899 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Hachet, O. & Ephrussi, A. Drosophila Y14 shuttles to the posterior of the oocyte and is required for oskar mRNA transport. Curr. Biol. 11, 1666?1674 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Gorlich, D. & Kutay, U. Transport between the cell nucleus and the cytoplasm. Annu. Rev. Cell Dev. Biol. 15, 607?660 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Mattaj, I. W. & Englmeier, L. Nucleocytoplasmic transport: the soluble phase. Annu. Rev. Biochem. 67, 265?306 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Nakielny, S. & Dreyfuss, G. Transport of proteins and RNAs in and out of the nucleus. Cell 99, 677?690 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Segref, A. et al. Mex67p, a novel factor for nuclear mRNA export, binds to both poly(A)+ RNA and nuclear pores. EMBO J. 16, 3256?3271 (1997).This paper identifies an essential cellular factor for nuclear mRNA export in yeast, called Mex67, through its genetic interaction with nucleoporin Nup85. In the thermosensitive mex67 mutant, accumulation of poly(A) RNA in intranuclear foci is detected shortly after a shift to the restrictive temperature. These results strongly indicate that Mex67 is likely to participate directly in the export of mRNA from the nucleus to the cytoplasm.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Gruter, P. et al. TAP, the human homolog of Mex67p, mediates CTE-dependent RNA export from the nucleus. Mol. Cell 1, 649?659 (1998).The constitutive transport element (CTE) of the type D retroviruses has been shown to promote nuclear export of unspliced viral RNAs. This paper identifies TAP as the cellular factor that specifically binds to wild-type CTE and mediates CTE-dependent export. As the excess amount of CTE blocks mRNA export and TAP can overcome this effect, TAP was thought to have a function in mRNA export, like its yeast homologue Mex67.

    Article  CAS  PubMed  Google Scholar 

  98. Katahira, J. et al. The Mex67p-mediated nuclear mRNA export pathway is conserved from yeast to human. EMBO J. 18, 2593?2609 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yoon, J. H., Love, D. C., Guhathakurta, A., Hanover, J. A. & Dhar, R. Mex67p of Schizosaccharomyces pombe interacts with Rae1p in mediating mRNA export. Mol. Cell. Biol. 20, 8767?8782 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bear, J. et al. Identification of novel import and export signals of human TAP, the protein that binds to the constitutive transport element of the type D retrovirus mRNAs. Mol. Cell. Biol. 19, 6306?6317 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Braun, I. C., Rohrbach, E., Schmitt, C. & Izaurralde, E. TAP binds to the constitutive transport element (CTE) through a novel RNA-binding motif that is sufficient to promote CTE-dependent RNA export from the nucleus. EMBO J. 18, 1953?1965 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kang, Y. & Cullen, B. R. The human Tap protein is a nuclear mRNA export factor that contains novel RNA-binding and nucleocytoplasmic transport sequences. Genes Dev. 13, 1126?1139 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tan, W., Zolotukhin, A. S., Bear, J., Patenaude, D. J. & Felber, B. K. The mRNA export in Caenorhabditis elegans is mediated by Ce-NXF-1, an ortholog of human TAP/NXF and Saccharomyces cerevisiae Mex67p. RNA 6, 1762?1772 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Braun, I. C., Herold, A., Rode, M., Conti, E. & Izaurralde, E. Overexpression of TAP/p15 heterodimers bypasses nuclear retention and stimulates nuclear mRNA export. J. Biol. Chem. 276, 20536?20543 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Guzik, B. W. et al. NXT1 (p15) is a crucial cellular cofactor in TAP-dependent export of intron-containing RNA in mammalian cells. Mol. Cell. Biol. 21, 2545?2554 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Levesque, L. et al. RNA export mediated by tap involves NXT1-dependent interactions with the nuclear pore complex. J. Biol. Chem. 276, 44953?44962 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Wiegand, H. L. et al. Formation of Tap/NXT1 heterodimers activates Tap-dependent nuclear mRNA export by enhancing recruitment to nuclear pore complexes. Mol. Cell. Biol. 22, 245?256 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Herold, A. et al. TAP (NXF1) belongs to a multigene family of putative RNA export factors with a conserved modular architecture. Mol. Cell. Biol. 20, 8996?9008 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Jun, L. et al. NXF5, a novel member of the nuclear RNA export factor family, is lost in a male patient with a syndromic form of mental retardation. Curr. Biol. 11, 1381?1391 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Fan, X. C. & Steitz, J. A. HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc. Natl Acad. Sci. USA 95, 15293?15298 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Brown, J. A. et al. A mutation in the Schizosaccharomyces pombe rae1 gene causes defects in poly(A)+ RNA export and in the cytoskeleton. J. Biol. Chem. 270, 7411?7419 (1995).

    Article  CAS  PubMed  Google Scholar 

  112. Murphy, R., Watkins, J. L. & Wente, S. R. GLE2, a Saccharomyces cerevisiae homologue of the Schizosaccharomyces pombe export factor RAE1, is required for nuclear pore complex structure and function. Mol. Biol. Cell 7, 1921?1937 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bharathi, A. et al. The human RAE1 gene is a functional homologue of Schizosaccharomyces pombe rae1 gene involved in nuclear export of Poly(A)+ RNA. Gene 198, 251?258 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Pritchard, C. E., Fornerod, M., Kasper, L. H. & van Deursen, J. M. RAE1 is a shuttling mRNA export factor that binds to a GLEBS-like NUP98 motif at the nuclear pore complex through multiple domains. J. Cell Biol. 145, 237?254 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Snay-Hodge, C. A., Colot, H. V., Goldstein, A. L. & Cole, C. N. Dbp5p/Rat8p is a yeast nuclear pore-associated DEAD-box protein essential for RNA export. EMBO J. 17, 2663?2676 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Tseng, S. S. et al. Dbp5p, a cytosolic RNA helicase, is required for poly(A)+ RNA export. EMBO J. 17, 2651?2662 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Huang, Y. & Steitz, J. A. Splicing factors SRp20 and 9G8 promote the nucleocytoplasmic export of mRNA. Mol. Cell 7, 899?905 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Yang, J., Bogerd, H. P., Wang, P. J., Page, D. C. & Cullen, B. R. Two closely related human nuclear export factors utilize entirely distinct export pathways. Mol. Cell 8, 397?406 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Chang, D. D. & Sharp, P. A. Regulation by HIV Rev depends upon recognition of splice sites. Cell 59, 789?795 (1989).

    Article  CAS  PubMed  Google Scholar 

  120. Legrain, P. & Rosbash, M. Some cis- and trans-acting mutants for splicing target pre-mRNA to the cytoplasm. Cell 57, 573?583 (1989).

    Article  CAS  PubMed  Google Scholar 

  121. Custodio, N. et al. Inefficient processing impairs release of RNA from the site of transcription. EMBO J. 18, 2855?2866 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Portman, D. S., O'Connor, J. P. & Dreyfuss, G. YRA1, an essential Saccharomyces cerevisiae gene, encodes a novel nuclear protein with RNA annealing activity. RNA 3, 527?537 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Strasser, K. & Hurt, E. Yra1p, a conserved nuclear RNA-binding protein, interacts directly with Mex67p and is required for mRNA export. EMBO J. 19, 410?420 (2000).This paper shows that an RNA-binding protein Yra1 binds directly to Mex67. Mutants of YRA1 are impaired in nuclear-poly(A)-RNA export at the restrictive temperature. These results indicate that Yra1 is the mRNA-export factor that bridges the export factor Mex67/Mtr2 to mRNA transport cargoes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Luo, M. L. et al. Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 413, 644?647 (2001).This paper shows that the conserved DEAD-box helicase UAP56, which is a splicing factor, interacts directly and specifically with Aly/REF. These data indicate that UAP56 can couple pre-mRNA splicing and mRNA export by recruiting Aly/REF to the spliced mRNP.

    Article  CAS  PubMed  Google Scholar 

  125. Strasser, K. & Hurt, E. Splicing factor Sub2p is required for nuclear mRNA export through its interaction with Yra1p. Nature 413, 648?652 (2001).This paper shows a genetic interaction in yeast between mRNA-export factor Yra1 and Sub2, a DEAD-box helicase involved in splicing. Sub2 and Mex67/Mtr2 bind to the same domains of Yra1, and compete with each other for binding. These results indicate that the splicing factor Sub2 (the yeast homologue of the mammalian UAP56) is also important in mRNA export, probably by recruiting Yra1 to the mRNA.

    Article  CAS  PubMed  Google Scholar 

  126. Jensen, T. H., Boulay, J., Rosbash, M. & Libri, D. The DECD box putative ATPase Sub2p is an early mRNA export factor. Curr. Biol. 11, 1711?1715 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Gatfield, D. et al. The DExH/D box protein HEL/UAP56 is essential for mRNA nuclear export in Drosophila. Curr. Biol. 11, 1716?1721 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Micklem, D. R. et al. The mago nashi gene is required for the polarisation of the oocyte and the formation of perpendicular axes in Drosophila. Curr. Biol. 7, 468?478 (1997).

    Article  CAS  PubMed  Google Scholar 

  129. Newmark, P. A., Mohr, S. E., Gong, L. & Boswell, R. E. mago nashi mediates the posterior follicle cell-to-oocyte signal to organize axis formation in Drosophila. Development 124, 3197?3207 (1997).

    CAS  PubMed  Google Scholar 

  130. Zhao, X. F., Nowak, N. J., Shows, T. B. & Aplan, P. D. MAGOH interacts with a novel RNA-binding protein. Genomics 63, 145?148 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Mingot, J. M., Kostka, S., Kraft, R., Hartmann, E. & Gorlich, D. Importin 13: a novel mediator of nuclear import and export. EMBO J. 20, 3685?3694 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Hentze, M. W. & Kulozik, A. E. A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96, 307?310 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. Wilusz, C. J., Wang, W. & Peltz, S. W. Curbing the nonsense: the activation and regulation of mRNA surveillance. Genes Dev. 15, 2781?2785 (2001).

    CAS  PubMed  Google Scholar 

  134. Neu-Yilik, G. et al. Splicing and 3′ end formation in the definition of nonsense-mediated decay-competent human β-globin mRNPs. EMBO J. 20, 532?540 (2001).By using human β-globin mRNA as a model system, this paper shows that the formation of nonsense-mediated mRNA decay-competent mRNP particles in higher eukaryotes depends on splicing, but does not require the presence of a poly(A) tail.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Cheng, J., Belgrader, P., Zhou, X. & Maquat, L. E. Introns are cis effectors of the nonsense-codon-mediated reduction in nuclear mRNA abundance. Mol. Cell. Biol. 14, 6317?6325 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Carter, M. S., Li, S. & Wilkinson, M. F. A splicing-dependent regulatory mechanism that detects translation signals. EMBO J. 15, 5965?5975 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Thermann, R. et al. Binary specification of nonsense codons by splicing and cytoplasmic translation. EMBO J. 17, 3484?3494 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sun, X., Moriarty, P. M. & Maquat, L. E. Nonsense-mediated decay of glutathione peroxidase 1 mRNA in the cytoplasm depends on intron position. EMBO J. 19, 4734?4744 (2000).This paper shows that a premature termination codon elicits nonsense-mediated mRNA decay when it is located more than 50?55 nt upstream of the last exon?exon junction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Nagy, E. & Maquat, L. E. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem. Sci. 23, 198?199 (1998).

    Article  CAS  PubMed  Google Scholar 

  140. Qian, L., Vu, M. N., Carter, M. S., Doskow, J. & Wilkinson, M. F. T cell receptor-β mRNA splicing during thymic maturation in vivo and in an inducible T cell clone in vitro. J. Immunol. 151, 6801?6814 (1993).

    CAS  PubMed  Google Scholar 

  141. Belgrader, P., Cheng, J. & Maquat, L. E. Evidence to implicate translation by ribosomes in the mechanism by which nonsense codons reduce the nuclear level of human triosephosphate isomerase mRNA. Proc. Natl Acad. Sci. USA 90, 482?486 (1993).

    Article  CAS  PubMed  Google Scholar 

  142. Li, S., Leonard, D. & Wilkinson, M. F. T cell receptor (TCR) mini-gene mRNA expression regulated by nonsense codons: a nuclear-associated translation-like mechanism. J. Exp. Med. 185, 985?992 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Naeger, L. K., Schoborg, R. V., Zhao, Q., Tullis, G. E. & Pintel, D. J. Nonsense mutations inhibit splicing of MVM RNA in cis when they interrupt the reading frame of either exon of the final spliced product. Genes Dev. 6, 1107?1119 (1992).

    Article  CAS  PubMed  Google Scholar 

  144. Dietz, H. C. & Kendzior, R. J. Jr. Maintenance of an open reading frame as an additional level of scrutiny during splice site selection. Nature Genet. 8, 183?188 (1994).

    Article  CAS  PubMed  Google Scholar 

  145. Li, S. & Wilkinson, M. F. Nonsense surveillance in lymphocytes? Immunity 8, 135?141 (1998).

    Article  CAS  PubMed  Google Scholar 

  146. Gersappe, A. & Pintel, D. J. A premature termination codon interferes with the nuclear function of an exon splicing enhancer in an open reading frame-dependent manner. Mol. Cell. Biol. 19, 1640?1650 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Moriarty, P. M., Reddy, C. C. & Maquat, L. E. Selenium deficiency reduces the abundance of mRNA for Se-dependent glutathione peroxidase 1 by a UGA-dependent mechanism likely to be nonsense codon-mediated decay of cytoplasmic mRNA. Mol. Cell. Biol. 18, 2932?2939 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Lund, E. & Dahlberg, J. E. Proofreading and aminoacylation of tRNAs before export from the nucleus. Science 282, 2082?2085 (1998).

    Article  CAS  PubMed  Google Scholar 

  149. Dostie, J., Lejbkowicz, F. & Sonenberg, N. Nuclear eukaryotic initiation factor 4E (eIF4E) colocalizes with splicing factors in speckles. J. Cell Biol. 148, 239?247 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Iborra, F. J., Jackson, D. A. & Cook, P. R. Coupled transcription and translation within nuclei of mammalian cells. Science 293, 1139?1142 (2001).

    Article  CAS  PubMed  Google Scholar 

  151. Ishigaki, Y., Li, X., Serin, G. & Maquat, L. E. Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20. Cell 106, 607?617 (2001).

    Article  CAS  PubMed  Google Scholar 

  152. Czaplinski, K. et al. The surveillance complex interacts with the translation release factors to enhance termination and degrade aberrant mRNAs. Genes Dev. 12, 1665?1677 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Leeds, P., Peltz, S. W., Jacobson, A. & Culbertson, M. R. The product of the yeast UPF1 gene is required for rapid turnover of mRNAs containing a premature translational termination codon. Genes Dev. 5, 2303?2314 (1991).

    Article  CAS  PubMed  Google Scholar 

  154. Cui, Y., Hagan, K. W., Zhang, S. & Peltz, S. W. Identification and characterization of genes that are required for the accelerated degradation of mRNAs containing a premature translational termination codon. Genes Dev. 9, 423?436 (1995).

    Article  CAS  PubMed  Google Scholar 

  155. Gonzalez, C. I., Ruiz-Echevarria, M. J., Vasudevan, S., Henry, M. F. & Peltz, S. W. The yeast hnRNP-like protein Hrp1/Nab4 marks a transcript for nonsense-mediated mRNA decay. Mol. Cell 5, 489?499 (2000).

    Article  CAS  PubMed  Google Scholar 

  156. Perlick, H. A., Medghalchi, S. M., Spencer, F. A., Kendzior, R. J. Jr & Dietz, H. C. Mammalian orthologues of a yeast regulator of nonsense transcript stability. Proc. Natl Acad. Sci. USA 93, 10928?10932 (1996).

    Article  CAS  PubMed  Google Scholar 

  157. Mendell, J. T., Medghalchi, S. M., Lake, R. G., Noensie, E. N. & Dietz, H. C. Novel Upf2p orthologues suggest a functional link between translation initiation and nonsense surveillance complexes. Mol. Cell. Biol. 20, 8944?8957 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Serin, G., Gersappe, A., Black, J. D., Aronoff, R. & Maquat, L. E. Identification and characterization of human orthologues to Saccharomyces cerevisiae Upf2 protein and Upf3 protein (Caenorhabditis elegans SMG-4). Mol. Cell. Biol. 21, 209?223 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Dietz, H. C. et al. The skipping of constitutive exons in vivo induced by nonsense mutations. Science 259, 680?683 (1993).

    Article  CAS  PubMed  Google Scholar 

  160. Lozano, F., Maertzdorf, B., Pannell, R. & Milstein, C. Low cytoplasmic mRNA levels of immunoglobulin κ light chain genes containing nonsense codons correlate with inefficient splicing. EMBO J. 13, 4617?4622 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Aoufouchi, S., Yelamos, J. & Milstein, C. Nonsense mutations inhibit RNA splicing in a cell-free system: recognition of mutant codon is independent of protein synthesis. Cell 85, 415?422 (1996).

    Article  CAS  PubMed  Google Scholar 

  162. Muhlemann, O. et al. Precursor RNAs harboring nonsense codons accumulate near the site of transcription. Mol. Cell 8, 33?43 (2001).

    Article  CAS  PubMed  Google Scholar 

  163. Reed, R. & Magni, K. A new view of mRNA export: separating the wheat from the chaff. Nature Cell Biol. 3, E201?E204 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to members of the Dreyfuss laboratory, especially J. Dostie, A. Gubitz, Z. Mourelatos and L. Wan, for critical reading of and comments on this manuscript. V.N.K. is supported by a BK21 Research Fellowship from the Ministry of Education and Human Resources Development of Korea. Work in G.D.'s laboratory is supported by grants from the National Institutes of Health and the Human Frontier Science Program Organization. G.D. is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, 19104-6148, Pennsylvania, USA

    Gideon Dreyfuss & Naoyuki Kataoka

  2. Institute for Molecular Biology and Genetics, School of Biological Science, Seoul National University, Seoul, Korea

    V. Narry Kim

Authors
  1. Gideon Dreyfuss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Narry Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naoyuki Kataoka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gideon Dreyfuss.

Related links

Related links

DATABASES

FlyBase:

HEL

mago nashi

oskar

Y14

 Interpro:

RNP

 LocusLink:

iron regulatory protein

Swiss-Prot

CRM1

Dbp5

β-globin

hnRNP A1

hnRNP H

hnRNP U

magoh

Mex67

PABPI

PABPII

RAE1

Ran

RNPS1

SRm160

Sub2

UPF1

UPF 2

Upf3

UPF3

UPF3a

UPF3b

FURTHER READING

messenger RNA in eukaryotes

messenger RNA in prokaryotes

mRNA splicing: role of snRNAs

RNA interactions in mRNA splicing

Glossary

PRE-mRNA

The primary transcript of the genomic DNA, which contains exons, introns and other sequences.

SPLICING

The removal of introns from the pre-mRNA.

TERMINATION CODONS

The stop signals for translation: UAA, UAG and UGA.

RNA POLYMERASE II

The enzyme that transcribes mRNA and most of the small nuclear RNAs (snRNAs) of eukaryotes, in conjunction with various transcription factors.

SMALL NUCLEAR RNPS

Low-molecular-weight RNAs, associated with proteins. They mediate the splicing of primary RNA transcripts.

POLY(A)

Newly synthesized mRNAs are poly-adenylated to generate a 3′ poly(A) tail. In eukaryotes, the number of residues added can vary from 50?250.

SR PROTEINS

A family of splicing factors, so-named because they are rich in serine (S) and arginine (R) residues. These proteins select splice sites and form part of the spliceosome complex.

POLYSOMES

Also known as polyribosomes. Two or more ribosomes that are attached to different points on the same strand of mRNA.

eIF4E

This is part of the translation-initiation complex, in which eIF4E is the cap-binding component.

LAMPBRUSH CHROMOSOMES

These are giant chromosomes that are found in oocytes ? generally in amphibians. These chromosomes contain large loops that are active in RNA synthesis.

BALBIANI RING

A 'puff' or bloated segment of a lampbrush chromosome that shows especially intense activity (in this case, RNA transcription).

NONSENSE-MEDIATED mRNA DECAY (NMD)

A pathway that ensures that mRNAs bearing premature stop codons are eliminated as templates for translation.

TRANSFER RNA

A small RNA molecule that is responsible for the transfer of specific amino acids to the growing end of a polypeptide chain during translation.

U snRNA

A uridine-rich small nuclear RNA.

NUCLEAR PORE COMPLEX

A protein complex that is involved in the import of proteins to the nucleus.

RNA INTERFERENCE

The process by which an introduced double-stranded RNA specifically silences the expression of genes through degradation of their cognate mRNAs.

SPLICEOSOME

A protein?U snRNA complex that is required for folding of the pre-mRNA into the correct conformation for the removal of introns.

DEAD-BOX FAMILY

A family of ATP-dependent helicases that can stabilize mRNA and facilitate translation.

OSKAR

A gene that is involved in determining cell fate in Drosophila . The oskar mRNA localizes to the posterior end of an oocyte.

3′ UNTRANSLATED REGION

Non-coding region that lies 3′ to the protein-coding part of an mRNA. This often contains sequences that are involved in RNA regulation.

GERM PLASM

A special cytoplasmic region in (dividing) eggs that contains primary germ-cell-determining factors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dreyfuss, G., Kim, V. & Kataoka, N. Messenger-RNA-binding proteins and the messages they carry. Nat Rev Mol Cell Biol 3, 195–205 (2002). https://doi.org/10.1038/nrm760

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm760

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing