An extensive network of coupling among gene expression machines

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Abstract

Gene expression in eukaryotes requires several multi-component cellular machines. Each machine carries out a separate step in the gene expression pathway, which includes transcription, several pre-messenger RNA processing steps and the export of mature mRNA to the cytoplasm. Recent studies lead to the view that, in contrast to a simple linear assembly line, a complex and extensively coupled network has evolved to coordinate the activities of the gene expression machines. The extensive coupling is consistent with a model in which the machines are tethered to each other to form ‘gene expression factories’ that maximize the efficiency and specificity of each step in gene expression.

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Figure 1: A complex network of coupled interactions in gene expression.
Figure 2: Gene expression factory model for coupling steps in gene expression.
Figure 3: Model for coupling splicing to mRNA export and nonsense-mediated decay.

References

  1. 1

    Bentley, D. Coupling RNA polymerase II transcription with pre-mRNA processing. Curr. Opin. Cell Biol. 11, 347–351 (1999).

  2. 2

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

  3. 3

    Proudfoot, N. Connecting transcription to messenger RNA processing. Trends Biochem. Sci. 25, 290–293 (2000).

  4. 4

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

  5. 5

    Cramer, P. et al. Coordination between transcription and pre-mRNA processing. FEBS Lett. 498, 179–182 (2001).

  6. 6

    Ptashne, M. & Gann, A. Genes and Signals (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2002).

  7. 7

    Dahmus, M. E. Reversible phosphorylation of the C-terminal domain of RNA polymerase II. J. Biol. Chem. 271, 19009–19012 (1996).

  8. 8

    Komarnitsky, P., Cho, E. J. & Buratowski, S. Different phosphorylated forms of RNA polymerase II and associated mRNA processing factors during transcription. Genes Dev. 14, 2452–2460 (2000).

  9. 9

    Cho, E. J., Kobor, M. S., Kim, M., Greenblatt, J. & Buratowski, S. Opposing effects of Ctk1 kinase and Fcp1 phosphatase at Ser 2 of the RNA polymerase II C-terminal domain. Genes Dev. 15, 3319–3329 (2001).

  10. 10

    Trigon, S. et al. Characterization of the residues phosphorylated in vitro by different C-terminal domain kinases. J. Biol. Chem. 273, 6769–6775 (1998).

  11. 11

    Price, D. H. P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol. Cell. Biol. 20, 2629–2634 (2000).

  12. 12

    McCracken, S. et al. 5′-Capping enzymes are targeted to pre-mRNA by binding to the phosphorylated carboxy-terminal domain of RNA polymerase II. Genes Dev. 11, 3306–3318 (1997).

  13. 13

    Cho, E. J., Takagi, T., Moore, C. R. & Buratowski, S. mRNA capping enzyme is recruited to the transcription complex by phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev. 11, 3319–3326 (1997).

  14. 14

    McCracken, S. et al. The C-terminal domain of RNA polymerase II couples mRNA processing to transcription. Nature 385, 357–361 (1997).

  15. 15

    Fong, N. & Bentley, D. L. Capping, splicing, and 3′ processing are independently stimulated by RNA polymerase II: different functions for different segments of the CTD. Genes Dev. 15, 1783–1795 (2001).

  16. 16

    Cramer, P., Bushnell, D. A. & Kornberg, R. D. Structural basis of transcription: RNA polymerase II at 2.8 angstrom resolution. Science 292, 1863–1876 (2001).

  17. 17

    Ho, C. K. & Shuman, S. Distinct roles for CTD Ser-2 and Ser-5 phosphorylation in the recruitment and allosteric activation of mammalian mRNA capping enzyme. Mol. Cell 3, 405–411 (1999).

  18. 18

    Schroeder, S. C., Schwer, B., Shuman, S. & Bentley, D. Dynamic association of capping enzymes with transcribing RNA polymerase II. Genes Dev. 14, 2435–2440 (2000).

  19. 19

    Cho, E. J., Rodriguez, C. R., Takagi, T. & Buratowski, S. Allosteric interactions between capping enzyme subunits and the RNA polymerase II carboxy-terminal domain. Genes Dev. 12, 3482–3487 (1998).

  20. 20

    Taube, R., Lin, X., Irwin, D., Fujinaga, K. & Peterlin, B. M. Interaction between P-TEFb and the C-terminal domain of RNA polymerase II activates transcriptional elongation from sites upstream or downstream of target genes. Mol. Cell. Biol. 22, 321–331 (2002).

  21. 21

    Wada, T., Takagi, T., Yamaguchi, Y., Watanabe, D. & Handa, H. Evidence that P-TEFb alleviates the negative effect of DSIF on RNA polymerase II-dependent transcription in vitro. EMBO J. 17, 7395–7403 (1998).

  22. 22

    Kim, J. B. & Sharp, P. A. Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase. J. Biol. Chem. 276, 12317–12323 (2001).

  23. 23

    Wen, Y. & Shatkin, A. J. Transcription elongation factor hSPT5 stimulates mRNA capping. Genes Dev. 13, 1774–1779 (1999).

  24. 24

    Fong, Y. W. & Zhou, Q. Stimulatory effect of splicing factors on transcriptional elongation. Nature 414, 929–933 (2001).

  25. 25

    Barboric, M., Nissen, R. M., Kanazawa, S., Jabrane-Ferrat, N. & Peterlin, B. M. NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol. Cell 8, 327–337 (2001).

  26. 26

    Kim, J. B., Yamaguchi, Y., Wada, T., Handa, H. & Sharp, P. A. Tat-SF1 protein associates with RAP30 and human SPT5 proteins. Mol. Cell. Biol. 19, 5960–5968 (1999).

  27. 27

    Yan, D. et al. CUS2, a yeast homolog of human Tat-SF1, rescues function of misfolded U2 through an unusual RNA recognition motif. Mol. Cell. Biol. 18, 5000–5009 (1998).

  28. 28

    Ares, M. Jr, Grate, L. & Pauling, M. H. A handful of intron-containing genes produces the lion's share of yeast mRNA. RNA 5, 1138–1139 (1999).

  29. 29

    Robert, F., Blanchette, M., Maes, O., Chabot, B. & Coulombe, B. A human RNA polymerase II-containing complex associated with factors necessary for spliceosome assembly. J. Biol. Chem. (in the press).

  30. 30

    Corden, J. L. & Patturajan, M. A CTD function linking transcription to splicing. Trends Biochem. Sci. 22, 413–416 (1997).

  31. 31

    Morris, D. P. & Greenleaf, A. L. The splicing factor, Prp40, binds the phosphorylated carboxyl-terminal domain of RNA polymerase II. J. Biol. Chem. 275, 39935–39943 (2000).

  32. 32

    Abovich, N. & Rosbash, M. Cross-intron bridging interactions in the yeast commitment complex are conserved in mammals. Cell 89, 403–412 (1997).

  33. 33

    Berget, S. M. Exon recognition in vertebrate splicing. J. Biol. Chem. 270, 2411–2414 (1995).

  34. 34

    Goldstrohm, A. C., Greenleaf, A. L. & Garcia-Blanco, M. A. Co-transcriptional splicing of pre-messenger RNAs: considerations for the mechanism of alternative splicing. Gene 277, 31–47 (2001).

  35. 35

    Lai, M. C., Teh, B. H. & Tarn, W. Y. A human papillomavirus E2 transcriptional activator. The interactions with cellular splicing factors and potential function in pre-mRNA processing. J. Biol. Chem. 274, 11832–11841 (1999).

  36. 36

    Ge, H. Si, Y. & Wolffe, A. P. A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2. Mol. Cell 2, 751–759 (1998).

  37. 37

    Monsalve, M. et al. Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1. Mol. Cell 6, 307–316 (2000).

  38. 38

    Martinez, E. et al. Human staga complex is a chromatin-acetylating transcription coactivator that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo. Mol. Cell. Biol. 21, 6782–6795 (2001).

  39. 39

    Graveley, B. R. Sorting out the complexity of SR protein functions. RNA 6, 1197–1211 (2000).

  40. 40

    Graveley, B. R., Hertel, K. J. & Maniatis, T. SR proteins are ‘locators’ of the RNA splicing machinery. Curr. Biol. 9, R6–R7 (1999).

  41. 41

    Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).

  42. 42

    Cramer, P., Pesce, C. G., Baralle, F. E. & Kornblihtt, A. R. Functional association between promoter structure and transcript alternative splicing. Proc. Natl Acad. Sci. USA 94, 11456–11460 (1997).

  43. 43

    Cramer, P. et al. Coupling of transcription with alternative splicing: RNA pol II promoters modulate SF2/ASF and 9G8 effects on an exonic splicing enhancer. Mol. Cell 4, 251–258 (1999).

  44. 44

    Kadener, S. et al. Antagonistic effects of T-Ag and VP16 reveal a role for RNA pol II elongation on alternative splicing. EMBO J. 20, 5759–5768 (2001).

  45. 45

    Eperon, L. P., Graham, I. R., Griffiths, A. D. & Eperon, I. C. Effects of RNA secondary structure on alternative splicing of pre-mRNA: is folding limited to a region behind the transcribing RNA polymerase? Cell 54, 393–401 (1988).

  46. 46

    Roberts, G. C., Gooding, C., Mak, H. Y., Proudfoot, N. J. & Smith, C. W. Co-transcriptional commitment to alternative splice site selection. Nucleic Acids Res. 26, 5568–5572 (1998).

  47. 47

    Lewis, J. D., Izaurralde, E., Jarmolowski, A., McGuigan, C. & Mattaj, I. W. A nuclear cap-binding complex facilitates association of U1 snRNP with the cap-proximal 5′ splice site. Genes Dev. 10, 1683–1698 (1996).

  48. 48

    Colot, H. V., Stutz, F. & Rosbash, M. The yeast splicing factor Mud13p is a commitment complex component and corresponds to CBP20, the small subunit of the nuclear cap-binding complex. Genes Dev. 10, 1699–1708 (1996).

  49. 49

    Vagner, S., Vagner, C. & Mattaj, I. W. The carboxyl terminus of vertebrate poly(A) polymerase interacts with U2AF 65 to couple 3′-end processing and splicing. Genes Dev. 14, 403–413 (2000).

  50. 50

    McCracken, S., Lambermon, M. & Blencowe, B. J. SRm160 splicing coactivator promotes transcript 3′-end cleavage. Mol. Cell. Biol. 22, 148–160 (2002).

  51. 51

    Reed, R. Mechanisms of fidelity in pre-mRNA splicing. Curr. Opin. Cell Biol. 12, 340–345 (2000).

  52. 52

    Proudfoot, N. J. How RNA polymerase II terminates transcription in higher eukaryotes. Trends Biochem. Sci. 14, 105–110 (1989).

  53. 53

    Birse, C. E., Minvielle-Sebastia, L., Lee, B. A., Keller, W. & Proudfoot, N. J. Coupling termination of transcription to messenger RNA maturation in yeast. Science 280, 298–301 (1998).

  54. 54

    McCracken, S. et al. Role of RNA polymerase II carboxy-terminal domain in coordinating transcription with RNA processing. Cold Spring Harbor Symp. Quant. Biol. 63, 301–309 (1998).

  55. 55

    Dye, M. J. & Proudfoot, N. J. Multiple transcript cleavage precedes polymerase release in termination by RNA polymerase II. Cell 105, 669–681 (2001).

  56. 56

    Osheim, Y. N., Proudfoot, N. J. & Beyer, A. L. EM visualization of transcription by RNA polymerase II: downstream termination requires a poly(A) signal but not transcript cleavage. Mol. Cell 3, 379–387 (1999).

  57. 57

    Tran, D. P., Kim, S. J., Park, N. J., Jew, T. M. & Martinson, H. G. Mechanism of poly(A) signal transduction to RNA polymerase II in vitro. Mol. Cell. Biol. 21, 7495–7508 (2001).

  58. 58

    Aranda, A. & Proudfoot, N. Transcriptional termination factors for RNA polymerase II in yeast. Mol. Cell 7, 1003–1011 (2001).

  59. 59

    Calvo, O. & Manley, J. L. Evolutionarily conserved interaction between CstF-64 and PC4 links transcription, polyadenylation, and termination. Mol. Cell 7, 1013–1023 (2001).

  60. 60

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

  61. 61

    Jensen, T. H., Patricio, K., McCarthy, T. & Rosbash, M. A block to mRNA nuclear export in S. cerevisiae leads to hyperadenylation of transcripts that accumulate at the site of transcription. Mol. Cell 7, 887–898 (2001).

  62. 62

    Gall, J. G. A role for Cajal bodies in assembly of the nuclear transcription machinery. FEBS Lett. 498, 164–167 (2001).

  63. 63

    Dundr, M. & Misteli, T. Functional architecture in the cell nucleus. Biochem. J. 356, 297–310 (2001).

  64. 64

    Sleeman, J. E. & Lamond, A. I. Newly assembled snRNPs associate with coiled bodies before speckles, suggesting a nuclear snRNP maturation pathway. Curr. Biol. 9, 1065–1074 (1999).

  65. 65

    Misteli, T., Caceres, J. F. & Spector, D. L. The dynamics of a pre-mRNA splicing factor in living cells. Nature 387, 523–527 (1997).

  66. 66

    Misteli, T. et al. Serine phosphorylation of SR proteins is required for their recruitment to sites of transcription in vivo. J. Cell. Biol. 143, 297–307 (1998).

  67. 67

    Misteli, T. & Spector, D. L. RNA polymerase II targets pre-mRNA splicing factors to transcription sites in vivo. Mol. Cell 3, 697–705 (1999).

  68. 68

    Phair, R. D. & Misteli, T. High mobility of proteins in the mammalian cell nucleus. Nature 404, 604–609 (2000).

  69. 69

    Iborra, F. J., Pombo, A., Jackson, D. A. & Cook, P. R. Active RNA polymerases are localized within discrete transcription “factories” in human nuclei. J. Cell Sci. 109, 1427–1436 (1996).

  70. 70

    Cook, P. R. The organization of replication and transcription. Science 284, 1790–1795 (1999).

  71. 71

    Wetterberg, I., Zhao, J., Masich, S., Wieslander, L. & Skoglund, U. In situ transcription and splicing in the Balbiani ring 3 gene. EMBO J. 20, 2564–2574 (2001).

  72. 72

    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).

  73. 73

    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).

  74. 74

    Zhou, Z. et al. The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 407, 401–405 (2000).

  75. 75

    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).

  76. 76

    Luo, M. L. et al. Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 413, 644–647 (2001).

  77. 77

    Strasser, K. & Hurt, E. Splicing factor Sub2p is required for nuclear mRNA export through its interaction with Yra1p. Nature 413, 648–652 (2001).

  78. 78

    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).

  79. 79

    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).

  80. 80

    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).

  81. 81

    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).

  82. 82

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

  83. 83

    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).

  84. 84

    Bachi, A. et al. The C-terminal domain of TAP interacts with the nuclear pore complex and promotes export of specific CTE-bearing RNA substrates. RNA 6, 136–158 (2000).

  85. 85

    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).

  86. 86

    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).

  87. 87

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

  88. 88

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

  89. 89

    Hilleren, P., McCarthy, T., Rosbash, M., Parker, R. & Jensen, T. H. Quality control of mRNA 3′-end processing is linked to the nuclear exosome. Nature 413, 538–542 (2001).

  90. 90

    Lei, E. P., Krebber, H. & Silver, P. A. Messenger RNAs are recruited for nuclear export during transcription. Genes Dev. 15, 1771–1782 (2001).

  91. 91

    Gross, S. & Moore, C. L. Rna15 interaction with the a-rich yeast polyadenylation signal is an essential step in mRNA 3′-end formation. Mol. Cell. Biol. 21, 8045–8055 (2001).

  92. 92

    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).

  93. 93

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

  94. 94

    Maquat, L. E. & Carmichael, G. G. Quality control of mRNA function. Cell 104, 173–176 (2001).

  95. 95

    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).

  96. 96

    Lykke-Andersen, J., Shu, M. D. & Steitz, J. A. Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon. Cell 103, 1121–1131 (2000).

  97. 97

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

  98. 98

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

  99. 99

    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).

  100. 100

    Czaplinski, K., Ruiz-Echevarria, M. J., Gonzalez, C. I. & Peltz, S. W. Should we kill the messenger? The role of the surveillance complex in translation termination and mRNA turnover. Bioessays 21, 685–696 (1999).

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Acknowledgements

We thank R. Axel, D. Bentley, S. Buratowski, B. Graveley, J. Manley, M. Ptashne and members of our labs for their comments on the manuscript. We also thank R. Hellmiss for the illustrations.

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Correspondence to Tom Maniatis or Robin Reed.

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