Control of mammalian gene expression by selective mRNA export

Nature Reviews Molecular Cell Biology

Volumn 16, Issue 7, 2015, Pages 431-442

  Wickramasinghe, Vihandha O ^a   Laskey, Ronald A ^b  

^a HUTCHISON MRC RESEARCH CENTRE   (United Kingdom)

^b UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATASE; BETA ACTIN; INITIATION FACTOR 4E; MESSENGER RNA; MESSENGER RNA PRECURSOR; NUCLEOPORIN; PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE; RIBONUCLEOPROTEIN; RNA HELICASE; SMALL NUCLEAR RIBONUCLEOPROTEIN; TRANSCRIPTION FACTOR NANOG; TRANSCRIPTION FACTOR SOX2; TRANSCRIPTOME; TREX 2 PROTEIN; UNCLASSIFIED DRUG; EXODEOXYRIBONUCLEASE;

CELL SURVIVAL; CYTOPLASM; DNA REPAIR; DROSOPHILA MELANOGASTER; GENE CONTROL; GENE EXPRESSION; HEMATOPOIESIS; HETEROCHROMATIN; HUMAN; NEOPLASM; NONHUMAN; NUCLEAR PORE; NUCLEAR PORE COMPLEX; PRIORITY JOURNAL; REVIEW; RNA PROCESSING; ACTIVE TRANSPORT; ANIMAL; GENE EXPRESSION REGULATION; GENETICS; MAMMAL; METABOLISM;

MAMMALIA;

ACTIVE TRANSPORT, CELL NUCLEUS; ANIMALS; CYTOPLASM; EXODEOXYRIBONUCLEASES; GENE EXPRESSION REGULATION; HUMANS; MAMMALS; NEOPLASMS; RIBONUCLEOPROTEINS; RNA, MESSENGER;

EID: 84934437553     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm4010     Document Type: Review

References (153)

1. Cheng, H. et al. Human mRNA export machinery recruited to the 5' end of mRNA. Cell 127, 1389-1400 (2006).
2. Masuda, S. et al. Recruitment of the human TREX complex to mRNA during splicing. Genes Dev. 19, 1512-1517 (2005).
3. Strasser, K. et al. TREX is a conserved complex coupling transcription with messenger RNA export. Nature 417, 304-308 (2002).
4. Zhou, Z. et al. The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 407, 401-405 (2000).
5. Jani, D. et al. Functional and structural characterization of the mammalian TREX-2 complex that links transcription with nuclear messenger RNA export. Nucleic Acids Res. 40, 4562-4573 (2012).
6. Ellisdon, A. M., Dimitrova, L., Hurt, E. & Stewart, M. Structural basis for the assembly and nucleic acid binding of the TREX-2 transcription-export complex. Nat. Struct. Mol. Biol. 19, 328-336 (2012).
7. Jani, D. et al. Sus1, Cdc31, and the Sac3 CID region form a conserved interaction platform that promotes nuclear pore association and mRNA export. Mol. Cell 33, 727-737 (2009). References 5-7 provide important insights into the molecular architecture of TREX-2.
8. Fischer, T. et al. Yeast centrin Cdc31 is linked to the nuclear mRNA export machinery. Nat. Cell Biol. 6, 840-848 (2004).
9. Fischer, T. et al. The mRNA export machinery requires the novel Sac3p-Thp1p complex to dock at the nucleoplasmic entrance of the nuclear pores. EMBO J. 21, 5843-5852 (2002).
10. 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).
11. Katahira, J. et al. The Mex67p-mediated nuclear mRNA export pathway is conserved from yeast to human. EMBO J. 18, 2593-2609 (1999).
12. Wickramasinghe, V. O. et al. mRNA export from mammalian cell nuclei is dependent on GANP. Curr. Biol. 20, 25-31 (2010).
13. Hautbergue, G. M., Hung, M. L., Golovanov, A. P., Lian, L. Y. & Wilson, S. A. Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP. Proc. Natl Acad. Sci. USA 105, 5154-5159 (2008).
14. Wickramasinghe, V. O. et al. Selective nuclear export of specific classes of mRNA from mammalian nuclei is promoted by GANP. Nucleic Acids Res. 42, 5059-5071 (2014). This study shows that components of TREX-2 specifically promote the nuclear export of transcripts encoding proteins that are required for gene expression.
15. Wickramasinghe, V. O. et al. Human inositol polyphosphate multikinase regulates transcript-selective nuclear mRNA export to preserve genome integrity. Mol. Cell 51, 737-750 (2013). This study shows that DNA repair can be regulated by selective mRNA export. The mechanism involves TREX component ALY and IPMK and its catalytic product PtdIns(3, 4, 5)P3.
16. Wang, L. et al. The THO complex regulates pluripotency gene mRNA export and controls embryonic stem cell self-renewal and somatic cell reprogramming. Cell Stem Cell 13, 676-690 (2013). In this study, the THO subcomplex of TREX is shown to regulate establishment of pluripotency by promoting the nuclear export of transcripts that encode stem cell specification factors.
17. Culjkovic-Kraljacic, B., Baguet, A., Volpon, L., Amri, A. & Borden, K. L. The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation. Cell Rep. 2, 207-215 (2012).
18. Guria, A. et al. Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts. RNA 17, 1048-1056 (2011).
19. Mancini, A. et al. THOC5/FMIP, an mRNA export TREX complex protein, is essential for hematopoietic primitive cell survival in vivo. BMC Biol. 8, 1 (2010).
20. Topisirovic, I. et al. Molecular dissection of the eukaryotic initiation factor 4E (eIF4E) export-competent RNP. EMBO J. 28, 1087-1098 (2009).
21. Katahira, J., Inoue, H., Hurt, E. & Yoneda, Y. Adaptor Aly and co-adaptor Thoc5 function in the Tap-p15-mediated nuclear export of HSP70 mRNA. EMBO J. 28, 556-567 (2009).
22. Culjkovic, B., Topisirovic, I., Skrabanek, L., Ruiz-Gutierrez, M. & Borden, K. L. eIF4E is a central node of an RNA regulon that governs cellular proliferation. J. Cell Biol. 175, 415-426 (2006). This is one of the first studies to demonstrate selectivity of mRNA export in mammals. eIF4E coordinately promotes the export of mRNA encoded by several genes that are involved in cellular proliferation. This selective pathway is dependent on CRM1, the main protein export receptor, which exports various other RNAs and does not depend on NXF1.
23. Bonnet, A. & Palancade, B. Regulation of mRNA trafficking by nuclear pore complexes. Genes 5, 767-791 (2014).
24. Nino, C. A., Herissant, L., Babour, A. & Dargemont, C. mRNA nuclear export in yeast. Chem. Rev. 113, 8523-8545 (2013).
25. Natalizio, B. J. & Wente, S. R. Postage for the messenger: designating routes for nuclear mRNA export. Trends Cell Biol. 23, 365-373 (2013).
26. Katahira, J. mRNA export and the TREX complex. Biochim. Biophys. Acta 1819, 507-513 (2012).
27. Tutucci, E. & Stutz, F. Keeping mRNPs in check during assembly and nuclear export. Nat. Rev. Mol. Cell Biol. 12, 377-384 (2011).
28. Rodriguez-Navarro, S. & Hurt, E. Linking gene regulation to mRNA production and export. Curr. Opin. Cell Biol. 23, 302-309 (2011).
29. Grunwald, D., Singer, R. H. & Rout, M. Nuclear export dynamics of RNA-protein complexes. Nature 475, 333-341 (2011).
30. Matera, A. G. & Wang, Z. A day in the life of the spliceosome. Nat. Rev. Mol. Cell Biol. 15, 108-121 (2014).
31. Bentley, D. L. Coupling mRNA processing with transcription in time and space. Nat. Rev. Genet. 15, 163-175 (2014).
32. Muller-McNicoll, M. & Neugebauer, K. M. How cells get the message: dynamic assembly and function of mRNA-protein complexes. Nat. Rev. Genet. 14, 275-287 (2013).
33. Brugiolo, M., Herzel, L. & Neugebauer, K. M. Counting on co-transcriptional splicing. F1000Prime Rep. 5, 9 (2013).
34. Dias, A. P., Dufu, K., Lei, H. & Reed, R. A role for TREX components in the release of spliced mRNA from nuclear speckle domains. Nat. Commun. 1, 97 (2010).
35. Molenaar, C., Abdulle, A., Gena, A., Tanke, H. J. & Dirks, R. W. Poly(A)+ RNAs roam the cell nucleus and pass through speckle domains in transcriptionally active and inactive cells. J. Cell Biol. 165, 191-202 (2004).
36. Lamond, A. I. & Spector, D. L. Nuclear speckles: a model for nuclear organelles. Nat. Rev. Mol. Cell Biol. 4, 605-612 (2003).
37. Huang, S., Deerinck, T. J., Ellisman, M. H. & Spector, D. L. In vivo analysis of the stability and transport of nuclear poly(A)+ RNA. J. Cell Biol. 126, 877-899 (1994).
38. Cisse, I. I. et al. Real-time dynamics of RNA polymerase II clustering in live human cells. Science 341, 664-667 (2013).
39. Zhao, Z. W. et al. Spatial organization of RNA polymerase II inside a mammalian cell nucleus revealed by reflected light-sheet superresolution microscopy. Proc. Natl Acad. Sci. USA 111, 681-686 (2014).
40. Osborne, S. L., Thomas, C. L., Gschmeissner, S. & Schiavo, G. Nuclear PtdIns(4, 5)P2 assembles in a mitotically regulated particle involved in pre-mRNA splicing. J. Cell Sci. 114, 2501-2511 (2001).
41. Boronenkov, I. V., Loijens, J. C., Umeda, M. & Anderson, R. A. Phosphoinositide signaling pathways in nuclei are associated with nuclear speckles containing pre-mRNA processing factors. Mol. Biol. Cell 9, 3547-3560 (1998).
42. Barlow, C. A., Laishram, R. S. & Anderson, R. A. Nuclear phosphoinositides: a signaling enigma wrapped in a compartmental conundrum. Trends Cell Biol. 20, 25-35 (2010).
43. Okada, M., Jang, S. W. & Ye, K. Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY. Proc. Natl Acad. Sci. USA 105, 8649-8654 (2008).
44. Shopland, L. S., Johnson, C. V., Byron, M., McNeil, J. & Lawrence, J. B. Clustering of multiple specific genes and gene-rich R-bands around SC-35 domains: evidence for local euchromatic neighborhoods. J. Cell Biol. 162, 981-990 (2003).
45. Oeffinger, M. & Zenklusen, D. To the pore and through the pore: a story of mRNA export kinetics. Biochim. Biophys. Acta 1819, 494-506 (2012).
46. Sheinberger, J. & Shav-Tal, Y. The dynamic pathway of nuclear RNA in eukaryotes. Nucleus 4, 195-205 (2013).
47. Siebrasse, J. P., Kaminski, T. & Kubitscheck, U. Nuclear export of single native mRNA molecules observed by light sheet fluorescence microscopy. Proc. Natl Acad. Sci. USA 109, 9426-9431 (2012).
48. Ma, J. et al. High-resolution three-dimensional mapping of mRNA export through the nuclear pore. Nat. Commun. 4, 2414 (2013).
49. Mor, A. et al. Dynamics of single mRNP nucleocytoplasmic transport and export through the nuclear pore in living cells. Nat. Cell Biol. 12, 543-552 (2010).
50. Grunwald, D. & Singer, R. H. In vivo imaging of labelled endogenous β-actin mRNA during nucleocytoplasmic transport. Nature 467, 604-607 (2010). References 47-50 describe the use of high-resolution imaging techniques to examine the kinetics of nuclear export of single mRNA molecules.
51. Shav-Tal, Y. et al. Dynamics of single mRNPs in nuclei of living cells. Science 304, 1797-1800 (2004).
52. Politz, J. C., Tuft, R. A., Pederson, T. & Singer, R. H. Movement of nuclear poly(A) RNA throughout the interchromatin space in living cells. Curr. Biol. 9, 285-291 (1999).
53. Ben-Ari, Y. et al. The life of an mRNA in space and time. J. Cell Sci. 123, 1761-1774 (2010).
54. Shibata, S., Matsuoka, Y. & Yoneda, Y. Nucleocytoplasmic transport of proteins and poly(A)+ RNA in reconstituted Tpr-less nuclei in living mammalian cells. Genes Cells 7, 421-434 (2002).
55. Krull, S. et al. Protein Tpr is required for establishing nuclear pore-associated zones of heterochromatin exclusion. EMBO J. 29, 1659-1673 (2010).
56. Umlauf, D. et al. The human TREX-2 complex is stably associated with the nuclear pore basket. J. Cell Sci. 12, 2656-2667 (2013).
57. Viphakone, N. et al. TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export. Nat. Commun. 3, 1006 (2012). This study provides insight into how TREX promotes mRNA export by driving NXF1 into a conformation that enables it to bind to mRNA.
58. Grant, R. P., Hurt, E., Neuhaus, D. & Stewart, M. Structure of the C-terminal FG-nucleoporin binding domain of Tap/NXF1. Nat. Struct. Biol. 9, 247-251 (2002).
59. Fribourg, S., Braun, I. C., Izaurralde, E. & Conti, E. Structural basis for the recognition of a nucleoporin FG repeat by the NTF2-like domain of the TAP/p15 mRNA nuclear export factor. Mol. Cell 8, 645-656 (2001).
60. Hulsmann, B. B., Labokha, A. A. & Gorlich, D. The permeability of reconstituted nuclear pores provides direct evidence for the selective phase model. Cell 150, 738-751 (2012).
61. Rajanala, K. & Nandicoori, V. K. Localization of nucleoporin Tpr to the nuclear pore complex is essential for Tpr mediated regulation of the export of unspliced RNA. PLoS ONE 7, e29921 (2012).
62. Coyle, J. H., Bor, Y. C., Rekosh, D. & Hammarskjold, M. L. The Tpr protein regulates export of mRNAs with retained introns that traffic through the Nxf1 pathway. RNA 17, 1344-1356 (2011).
63. Yap, K., Lim, Z. Q., Khandelia, P., Friedman, B. & Makeyev, E. V. Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention. Genes Dev. 26, 1209-1223 (2012).
64. von Moeller, H., Basquin, C. & Conti, E. The mRNA export protein DBP5 binds RNA and the cytoplasmic nucleoporin NUP214 in a mutually exclusive manner. Nat. Struct. Mol. Biol. 16, 247-254 (2009).
65. Montpetit, B. et al. A conserved mechanism of DEAD-box ATPase activation by nucleoporins and InsP6 in mRNA export. Nature 472, 238-242 (2011).
66. Weirich, C. S. et al. Activation of the DExD/H-box protein Dbp5 by the nuclear-pore protein Gle1 and its coactivator InsP6 is required for mRNA export. Nat. Cell Biol. 8, 668-676 (2006).
67. Noble, K. N. et al. The Dbp5 cycle at the nuclear pore complex during mRNA export II: nucleotide cycling and mRNP remodeling by Dbp5 are controlled by Nup159 and Gle1. Genes Dev. 25, 1065-1077 (2011).
68. Hodge, C. A. et al. The Dbp5 cycle at the nuclear pore complex during mRNA export I: dbp5 mutants with defects in RNA binding and ATP hydrolysis define key steps for Nup159 and Gle1. Genes Dev. 25, 1052-1064 (2011).
69. Folkmann, A. W., Noble, K. N., Cole, C. N. & Wente, S. R. Dbp5, Gle1-IP6 and Nup159: a working model for mRNP export. Nucleus 2, 540-548 (2011).
70. Alcazar-Roman, A. R., Tran, E. J., Guo, S. & Wente, S. R. Inositol hexakisphosphate and Gle1 activate the DEAD-box protein Dbp5 for nuclear mRNA export. Nat. Cell Biol. 8, 711-716 (2006).
71. Dufu, K. et al. ATP is required for interactions between UAP56 and two conserved mRNA export proteins, Aly and CIP29, to assemble the TREX complex. Genes Dev. 24, 2043-2053 (2010). This study defines the molecular interactions that are involved in the assembly of TREX and suggests that the assembly process is ATP dependent.
72. Jimeno, S., Rondon, A. G., Luna, R. & Aguilera, A. The yeast THO complex and mRNA export factors link RNA metabolism with transcription and genome instability. EMBO J. 21, 3526-3535 (2002).
73. Chavez, S. et al. A protein complex containing Tho2, Hpr1, Mft1 and a novel protein, Thp2, connects transcription elongation with mitotic recombination in Saccharomyces cerevisiae. EMBO J. 19, 5824-5834 (2000).
74. 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).
75. Stutz, F. et al. REF, an evolutionary conserved family of hnRNP-like proteins, interacts with TAP/Mex67p and participates in mRNA nuclear export. RNA 6, 638-650 (2000).
76. Rehwinkel, J. et al. Genome-wide analysis of mRNAs regulated by the THO complex in Drosophila melanogaster. Nat. Struct. Mol. Biol. 11, 558-566 (2004).
77. Farny, N. G., Hurt, J. A. & Silver, P. A. Definition of global and transcript-specific mRNA export pathways in metazoans. Genes Dev. 22, 66-78 (2008).
78. Luo, M. L. et al. Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 413, 644-647 (2001).
79. Strasser, K. & Hurt, E. Splicing factor Sub2p is required for nuclear mRNA export through its interaction with Yra1p. Nature 413, 648-652 (2001).
80. Chang, C. T. et al. Chtop is a component of the dynamic TREX mRNA export complex. EMBO J. 32, 473-486 (2013).
81. Folco, E. G., Lee, C. S., Dufu, K., Yamazaki, T. & Reed, R. The proteins PDIP3 and ZC11A associate with the human TREX complex in an ATP-dependent manner and function in mRNA export. PloS ONE 7, e43804 (2012).
82. Hautbergue, G. M. et al. UIF, a new mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA. Curr. Biol. 19, 1918-1924 (2009).
83. Chi, B. et al. Aly and THO are required for assembly of the human TREX complex and association of TREX components with the spliced mRNA. Nucleic Acids Res. 41, 1294-1306 (2013).
84. Pena, A. et al. Architecture and nucleic acids recognition mechanism of the THO complex, an mRNP assembly factor. EMBO J. 31, 1605-1616 (2012).
85. Zhou, Z., Licklider, L. J., Gygi, S. P. & Reed, R. Comprehensive proteomic analysis of the human spliceosome. Nature 419, 182-185 (2002).
86. Singh, G. et al. The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell 151, 750-764 (2012).
87. Huang, Y. & Steitz, J. A. SRprises along a messenger's journey. Mol. Cell 17, 613-615 (2005).
88. Huang, Y., Yario, T. A. & Steitz, J. A. A molecular link between SR protein dephosphorylation and mRNA export. Proc. Natl Acad. Sci. USA 101, 9666-9670 (2004).
89. Huang, Y. & Steitz, J. A. Splicing factors SRp20 and 9G8 promote the nucleocytoplasmic export of mRNA. Mol. Cell 7, 899-905 (2001).
90. Huang, Y., Gattoni, R., Stevenin, J. & Steitz, J. A. SR splicing factors serve as adapter proteins for TAP-dependent mRNA export. Mol. Cell 11, 837-843 (2003).
91. Lei, H., Zhai, B., Yin, S., Gygi, S. & Reed, R. Evidence that a consensus element found in naturally intronless mRNAs promotes mRNA export. Nucleic Acids Res. 41, 2517-2525 (2013).
92. Narita, T. et al. NELF interacts with CBC and participates in 3' end processing of replication-dependent histone mRNAs. Mol. Cell 26, 349-365 (2007).
93. Sullivan, K. D., Mullen, T. E., Marzluff, W. F. & Wagner, E. J. Knockdown of SLBP results in nuclear retention of histone mRNA. RNA 15, 459-472 (2009).
94. Hieronymus, H. & Silver, P. A. Genome-wide analysis of RNA-protein interactions illustrates specificity of the mRNA export machinery. Nat. Genet. 33, 155-161 (2003). References 76 and 94 provide the first evidence that mRNA export can be selective in yeast and in D. melanogaster.
95. Hieronymus, H. & Silver, P. A. A systems view of mRNP biology. Genes Dev. 18, 2845-2860 (2004).
96. Herold, A., Teixeira, L. & Izaurralde, E. Genome-wide analysis of nuclear mRNA export pathways in Drosophila. EMBO J. 22, 2472-2483 (2003).
97. Tuck, A. C. & Tollervey, D. A transcriptome-wide atlas of RNP composition reveals diverse classes of mRNAs and lncRNAs. Cell 154, 996-1009 (2013).
98. Baejen, C. et al. Transcriptome maps of mRNP biogenesis factors define pre-mRNA recognition. Mol. Cell 55, 745-757 (2014).
99. Meinel, D. M. et al. Recruitment of TREX to the transcription machinery by its direct binding to the phospho-CTD of RNA polymerase II. PLoS Genet. 9, e1003914 (2013).
100. Gomez-Gonzalez, B. et al. Genome-wide function of THO/TREX in active genes prevents R-loop-dependent replication obstacles. EMBO J. 30, 3106-3119 (2011).
101. Stubbs, S. H. & Conrad, N. K. Depletion of REF/Aly alters gene expression and reduces RNA polymerase II occupancy. Nucleic Acids Res. 43, 504-519 (2015).
102. Rodriguez-Navarro, S. et al. Sus1, a functional component of the SAGA histone acetylase complex and the nuclear pore-associated mRNA export machinery. Cell 116, 75-86 (2004).
103. Cabal, G. G. et al. SAGA interacting factors confine sub-diffusion of transcribed genes to the nuclear envelope. Nature 441, 770-773 (2006).
104. Wickramasinghe, V. O. et al. MCM3AP is transcribed from a promoter within an intron of the overlapping gene for GANP. J. Mol. Biol. 406, 355-361 (2011).
105. Singh, S. K. et al. GANP regulates recruitment of AID to immunoglobulin variable regions by modulating transcription and nucleosome occupancy. Nat. Commun. 4, 1830 (2013).
106. Hutten, S. & Kehlenbach, R. H. CRM1-mediated nuclear export: to the pore and beyond. Trends Cell Biol. 17, 193-201 (2007).
107. Culjkovic-Kraljacic, B. & Borden, K. L. Aiding and abetting cancer: mRNA export and the nuclear pore. Trends Cell Biol. 23, 328-335 (2013).
108. Kohler, A. & Hurt, E. Exporting RNA from the nucleus to the cytoplasm. Nat. Rev. Mol. Cell Biol. 8, 761-773 (2007).
109. McCloskey, A., Taniguchi, I., Shinmyozu, K. & Ohno, M. hnRNP C tetramer measures RNA length to classify RNA polymerase II transcripts for export. Science 335, 1643-1646 (2012).
110. Brennan, C. M., Gallouzi, I. E. & Steitz, J. A. Protein ligands to HuR modulate its interaction with target mRNAs in vivo. J. Cell Biol. 151, 1-14 (2000).
111. 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).
112. Assouline, S. et al. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood 114, 257-260 (2009).
113. Culjkovic, B. et al. The eIF4E RNA regulon promotes the Akt signaling pathway. J. Cell Biol. 181, 51-63 (2008).
114. Blackinton, J. G. & Keene, J. D. Post-transcriptional RNA regulons affecting cell cycle and proliferation. Semin. Cell Dev. Biol. 34, 44-54 (2014).
115. Keene, J. D. & Tenenbaum, S. A. Eukaryotic mRNPs may represent posttranscriptional operons. Mol. Cell 9, 1161-1167 (2002).
116. Keene, J. D. RNA regulons: coordination of post-transcriptional events. Nat. Rev. Genet. 8, 533-543 (2007).
117. Maag, D. et al. Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB. Proc. Natl Acad. Sci. USA 108, 1391-1396 (2011).
118. Resnick, A. C. et al. Inositol polyphosphate multikinase is a nuclear PI3-kinase with transcriptional regulatory activity. Proc. Natl Acad. Sci. USA 102, 12783-12788 (2005).
119. Saiardi, A. et al. Mammalian inositol polyphosphate multikinase synthesizes inositol 1, 4, 5-trisphosphate and an inositol pyrophosphate. Proc. Natl Acad. Sci. USA 98, 2306-2311 (2001).
120. Zhang, X. et al. Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell 135, 1017-1027 (2008).
121. Chakraborty, P. et al. Nucleoporin levels regulate cell cycle progression and phase-specific gene expression. Dev. Cell 15, 657-667 (2008).
122. Faria, A. M. et al. The nucleoporin Nup96 is required for proper expression of interferon-regulated proteins and functions. Immunity 24, 295-304 (2006).
123. Cooper, T. A., Wan, L. & Dreyfuss, G. RNA and disease. Cell 136, 777-793 (2009).
124. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011).
125. Quesada, V. et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat. Genet. 44, 47-52 (2012).
126. Yoshida, K. et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478, 64-69 (2011).
127. Papaemmanuil, E. et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. New Engl. J. Med. 365, 1384-1395 (2011).
128. Fujimura, S. et al. Increased expression of germinal center-associated nuclear protein RNA-primase is associated with lymphomagenesis. Cancer Res. 65, 5925-5934 (2005).
129. Dominguez-Sanchez, M. S., Saez, C., Japon, M. A., Aguilera, A. & Luna, R. Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers. BMC Cancer 11, 77 (2011).
130. Saito, Y. et al. ALY as a potential contributor to metastasis in human oral squamous cell carcinoma. J. Cancer Res. Clin. Oncol. 139, 585-594 (2013).
131. Choong, M. L. et al. An integrated approach in the discovery and characterization of a novel nuclear protein over-expressed in liver and pancreatic tumors. FEBS Lett. 496, 109-116 (2001).
132. Guo, S. et al. Linking transcriptional elongation and messenger RNA export to metastatic breast cancers. Cancer Res. 65, 3011-3016 (2005).
133. Wendel, H. G. et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428, 332-337 (2004).
134. Lazaris-Karatzas, A., Montine, K. S. & Sonenberg, N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature 345, 544-547 (1990).
135. Nousiainen, H. O. et al. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat. Genet. 40, 155-157 (2008).
136. Kaneb, H. M. et al. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Hum. Mol. Genet. 24, 1363-1373 (2014).
137. Herva, R., Conradi, N. G., Kalimo, H., Leisti, J. & Sourander, P. A syndrome of multiple congenital contractures: neuropathological analysis on five fetal cases. Am. J. Med. Genet. 29, 67-76 (1988).
138. Herva, R., Leisti, J., Kirkinen, P. & Seppanen, U. A lethal autosomal recessive syndrome of multiple congenital contractures. Am. J. Med. Genet. 20, 431-439 (1985).
139. Folkmann, A. W. et al. Gle1 functions during mRNA export in an oligomeric complex that is altered in human disease. Cell 155, 582-593 (2013). This study shows that mutations in the gene encoding mRNA export factor GLE1 that occur in motor neuron disease affect its oligomerization and shuttling, which disrupts efficient nuclear export of mRNA at nuclear pores.
140. Aguilera, A. & Garcia-Muse, T. R loops: from transcription byproducts to threats to genome stability. Mol. Cell 46, 115-124 (2012).
141. Huertas, P. & Aguilera, A. Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol. Cell 12, 711-721 (2003).
142. Gonzalez-Aguilera, C. et al. The THP1-SAC3-SUS1-CDC31 complex works in transcription elongation-mRNA export preventing RNA-mediated genome instability. Mol. Biol. Cell 19, 4310-4318 (2008).
143. Dominguez-Sanchez, M. S., Barroso, S., Gomez-Gonzalez, B., Luna, R. & Aguilera, A. Genome instability and transcription elongation impairment in human cells depleted of THO/TREX. PLoS Genet. 7, e1002386 (2011).
144. Bhatia, V. et al. BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature 511, 362-365 (2014).
145. Ori, A. et al. Cell type-specific nuclear pores: a case in point for context-dependent stoichiometry of molecular machines. Mol. Syst. Biol. 9, 648 (2013).
146. Forler, D. et al. RanBP2/Nup358 provides a major binding site for NXF1-p15 dimers at the nuclear pore complex and functions in nuclear mRNA export. Mol. Cell. Biol. 24, 1155-1167 (2004).
147. Ullman, K. S., Shah, S., Powers, M. A. & Forbes, D. J. The nucleoporin Nup153 plays a critical role in multiple types of nuclear export. Mol. Biol. Cell 10, 649-664 (1999).
148. Speese, S. D. et al. Nuclear envelope budding enables large ribonucleoprotein particle export during synaptic Wnt signaling. Cell 149, 832-846 (2012).
149. York, J. D., Odom, A. R., Murphy, R., Ives, E. B. & Wente, S. R. A phospholipase C-dependent inositol polyphosphate kinase pathway required for efficient messenger RNA export. Science 285, 96-100 (1999).
150. Resendes, K. K., Rasala, B. A. & Forbes, D. J. Centrin 2 localizes to the vertebrate nuclear pore and plays a role in mRNA and protein export. Mol. Cell. Biol. 28, 1755-1769 (2008).
151. Faza, M. B. et al. Sem1 is a functional component of the nuclear pore complex-associated messenger RNA export machinery. J. Cell Biol. 184, 833-846 (2009).
152. Wilmes, G. M. et al. A genetic interaction map of RNA-processing factors reveals links between Sem1/Dss1-containing complexes and mRNA export and splicing. Mol. Cell 32, 735-746 (2008).
153. Mannen, T., Andoh, T. & Tani, T. Dss1 associating with the proteasome functions in selective nuclear mRNA export in yeast. Biochem. Biophys. Res. Commun. 365, 664-671 (2008).