Abstract
The presence of a nuclear envelope, also known as nuclear membrane, defines the structural framework of all eukaryotic cells by separating the nucleus, which contains the genetic material, from the cytoplasm where the synthesis of proteins takes place. Translation of proteins in Eukaryotes is thus dependent on the active transport of DNA-encoded RNA molecules through pores embedded within the nuclear membrane. Several mechanisms are involved in this process generally referred to as RNA nuclear export or nucleocytoplasmic transport of RNA. The regulated expression of genes requires the nuclear export of protein-coding messenger RNA molecules (mRNAs) as well as non-coding RNAs (ncRNAs) together with proteins and pre-assembled ribosomal subunits. The nuclear export of mRNAs is intrinsically linked to the co-transcriptional processing of nascent transcripts synthesized by the RNA polymerase II. This functional coupling is essential for the survival of cells allowing for timely nuclear export of fully processed transcripts, which could otherwise cause the translation of abnormal proteins such as the polymeric repeat proteins produced in some neurodegenerative diseases. Alterations of the mRNA nuclear export pathways can also lead to genome instability and to various forms of cancer. This chapter will describe the molecular mechanisms driving the nuclear export of RNAs with a particular emphasis on mRNAs. It will also review their known alterations in neurological disorders and cancer, and the recent opportunities they offer for the potential development of novel therapeutic strategies.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bañez-Coronel M, Ayhan F, Tarabochia AD, Zu T, Perez BA, Tusi SK et al (2015) RAN translation in Huntington disease. Neuron 88(4):667–677
Beaulieu CL, Huang L, Innes AM, Akimenko M-A, Puffenberger EG, Schwartz C et al (2013) Intellectual disability associated with a homozygous missense mutation in THOC6. Orphanet J Rare Dis 8:62
Boeynaems S, Bogaert E, Van Damme P, Van Den Bosch L (2016) Inside out: the role of nucleocytoplasmic transport in ALS and FTLD. Acta Neuropathol 132(2):159–173
Chakraborty P, Wang Y, Wei J-H, van Deursen J, Yu H, Malureanu L et al (2008) Nucleoporin levels regulate cell cycle progression and phase-specific gene expression. Dev Cell 15(5):657–667
Chang C-T, Hautbergue GM, Walsh MJ, Viphakone N, van Dijk TB, Philipsen S et al (2013) Chtop is a component of the dynamic TREX mRNA export complex. EMBO J 32(3):473–486
Charoensawan V, Janga SC, Bulyk ML, Babu MM, Teichmann SA (2012) DNA sequence preferences of transcriptional activators correlate more strongly than repressors with nucleosomes. Mol Cell 47(2):183–192
Cheng H, Dufu K, Lee C-S, Hsu JL, Dias A, Reed R (2006) Human mRNA export machinery recruited to the 5′ end of mRNA. Cell 127(7):1389–1400
Cooper-Knock J, Walsh MJ, Higginbottom A, Robin Highley J, Dickman MJ, Edbauer D et al (2014) Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137(Pt 7):2040–2051
Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KLB (2006) eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol 175(3):415–426
Culjkovic-Kraljacic B, Baguet A, Volpon L, Amri A, Borden KLB (2012) The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation. Cell Rep 2(2):207–215
Culjkovic-Kraljacic B, Borden KLB (2013) Aiding and abetting cancer: mRNA export and the nuclear pore. Trends Cell Biol 23(7):328–335
Dever TE, Green R (2012) The elongation, termination, and recycling phases of translation in eukaryotes. Cold Spring Harb Perspect Biol 4(7):a013706
Di Gregorio E, Bianchi FT, Schiavi A, Chiotto AMA, Rolando M, Verdun di Cantogno L et al (2013) A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia. J Med Genet 50(8):543–551
DomÃnguez-Sánchez MS, Sáez C, Japón MA, Aguilera A, Luna R (2011) Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers. BMC Cancer 11:77
Dufu K, Livingstone MJ, Seebacher J, Gygi SP, Wilson SA, Reed R (2010) ATP is required for interactions between UAP56 and two conserved mRNA export proteins, Aly and CIP29, to assemble the TREX complex. Genes Dev 24(18):2043–2053
Fischer T, Strässer K, Rácz A, RodrÃguez-Navarro S, Oppizzi M, Ihrig P et al (2002) The mRNA export machinery requires the novel Sac3p-Thp1p complex to dock at the nucleoplasmic entrance of the nuclear pores. EMBO J 21(21):5843–5852
Folkmann AW, Collier SE, Zhan X, Aditi O, Wente SR (2013) Gle1 functions during mRNA export in an oligomeric complex that is altered in human disease. Cell 155(3):582–593
Folkmann AW, Noble KN, Cole CN, Wente SR (2011) Dbp5, Gle1-IP6 and Nup159: a working model for mRNP export. Nucleus 2(6):540–548
Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee K-H et al (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525(7567):129–133
Fujimura S, Xing Y, Takeya M, Yamashita Y, Ohshima K, Kuwahara K et al (2005) Increased expression of germinal center-associated nuclear protein RNA-primase is associated with lymphomagenesis. Cancer Res 65(13):5925–5934
Garcia-Lopez A, Monferrer L, Garcia-Alcover I, Vicente-Crespo M, Alvarez-Abril MC, Artero RD (2008) Genetic and chemical modifiers of a CUG toxicity model in Drosophila. PLoS One 3(2):e1595
Gatfield D, Izaurralde E (2002) REF1/Aly and the additional exon junction complex proteins are dispensable for nuclear mRNA export. J Cell Biol 159(4):579–588
Gerstberger S, Hafner M, Tuschl T (2014) A census of human RNA-binding proteins. Nat Rev Genet 15(12):829–845
Girard C, Will CL, Peng J, Makarov EM, Kastner B, Lemm I et al (2012) Post-transcriptional spliceosomes are retained in nuclear speckles until splicing completion. Nat Commun 3:994
Graff JR, Konicek BW, Carter JH, Marcusson EG (2008) Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res 68(3):631–634
Griaud F, Pierce A, Gonzalez Sanchez MB, Scott M, Abraham SA, Holyoake TL et al (2013) A pathway from leukemogenic oncogenes and stem cell chemokines to RNA processing via THOC5. Leukemia 27(4):932–940
Hautbergue GM (2016) Widespread RNA dysregulation in neurodegeneration: challenges and opportunities. Austin Neurol 1(1):1002
Hautbergue GM, Hung M-L, Golovanov AP, Lian L-Y, Wilson SA (2008) Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP. Proc Natl Acad Sci U S A 105(13):5154–5159
Hautbergue GM, Hung M-L, Walsh MJ, Snijders APL, Chang C-T, Jones R et al (2009) UIF, a new mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA. Curr Biol 19(22):1918–1924
Heath CG, Viphakone N, Wilson SA (2016) The role of TREX in gene expression and disease. Biochem J 473(19):2911–2935
Herold A, Suyama M, Rodrigues JP, Braun IC, Kutay U, Carmo-Fonseca M et al (2000) TAP (NXF1) belongs to a multigene family of putative RNA export factors with a conserved modular architecture. Mol Cell Biol 20(23):8996–9008
Hough LE, Dutta K, Sparks S, Temel DB, Kamal A, Tetenbaum-Novatt J et al (2015) The molecular mechanism of nuclear transport revealed by atomic-scale measurements. elife 15:4
Hsin J-P, Manley JL (2012) The RNA polymerase II CTD coordinates transcription and RNA processing. Genes Dev 26(19):2119–2137
Huang Y, Gattoni R, Stevenin J, Steitz JA (2003) SR splicing factors serve as adapter proteins for TAP-dependent mRNA export. Mol Cell 11(3):837–843
Hung M-L, Hautbergue GM, Snijders APL, Dickman MJ, Wilson SA (2010) Arginine methylation of REF/ALY promotes efficient handover of mRNA to TAP/NXF1. Nucleic Acids Res 38(10):3351–3361
Hutten S, Kehlenbach RH (2007) CRM1-mediated nuclear export: to the pore and beyond. Trends Cell Biol 17(4):193–201
Jin P, Duan R, Qurashi A, Qin Y, Tian D, Rosser TC et al (2007) Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron 55(4):556–564
Jung H, Yoon BC, Holt CE (2012) Axonal mRNA localization and local protein synthesis in nervous system assembly, maintenance and repair. Nat Publ Group 13(5):308–324
Kageshita T, Kuwahara K, Oka M, Ma D, Ono T, Sakaguchi N (2006) Increased expression of germinal center-associated nuclear protein (GANP) is associated with malignant transformation of melanocytes. J Dermatol Sci 42(1):55–63
Kaneb HM, Folkmann AW, Belzil VV, Jao L-E, Leblond CS, Girard SL et al (2015) Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Hum Mol Genet 24(5):1363–1373
Katahira J, Inoue H, Hurt E, Yoneda Y (2009) Adaptor Aly and co-adaptor Thoc5 function in the Tap-p15-mediated nuclear export of HSP70 mRNA. EMBO J 28(5):556–567
Kilchert C, Wittmann S, Vasiljeva L (2016) The regulation and functions of the nuclear RNA exosome complex. Nat Rev Mol Cell Biol 17(4):227–239
Knockenhauer KE, Schwartz TU (2016) The nuclear pore complex as a flexible and dynamic gate. Cell 164(6):1162–1171
Köhler A, Hurt E (2007) Exporting RNA from the nucleus to the cytoplasm. Nat Rev Mol Cell Biol 8(10):761–773
Köhler A, Hurt E (2010) Gene regulation by nucleoporins and links to cancer. Mol Cell 38(1):6–15
Kumar R, Corbett MA, van Bon BWM, Woenig JA, Weir L, Douglas E et al (2015) THOC2 mutations implicate mRNA-export pathway in X-linked intellectual disability. Am J Hum Genet 97(2):302–310
Li Y, Lin AW, Zhang X, Wang Y, Wang X, Goodrich DW (2007) Cancer cells and normal cells differ in their requirements for Thoc1. Cancer Res 67(14):6657–6664
Lim RYH, Fahrenkrog B, Köser J, Schwarz-Herion K, Deng J, Aebi U (2007) Nanomechanical basis of selective gating by the nuclear pore complex. Science 318(5850):640–643
Longman D, Johnstone IL, Cáceres JF (2003) The Ref/Aly proteins are dispensable for mRNA export and development in Caenorhabditis elegans. RNA 9(7):881–891
Loureiro JR, Oliveira CL, Silveira I (2016) Unstable repeat expansions in neurodegenerative diseases: nucleocytoplasmic transport emerges on the scene. Neurobiol Aging 39:174–183
Luna R, Gaillard H, González-Aguilera C, Aguilera A (2008) Biogenesis of mRNPs: integrating different processes in the eukaryotic nucleus. Chromosoma 117(4):319–331
Lund MK, Guthrie C (2005) The DEAD-box protein Dbp5p is required to dissociate Mex67p from exported mRNPs at the nuclear rim. Mol Cell 20(4):645–651
Luo ML, Zhou Z, Magni K, Christoforides C, Rappsilber J, Mann M et al (2001) Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 413(6856):644–647
Masuda S, Das R, Cheng H, Hurt E, Dorman N, Reed R (2005) Recruitment of the human TREX complex to mRNA during splicing. Genes Dev 19(13):1512–1517
Milles S, Mercadante D, Aramburu IV, Jensen MR, Banterle N, Koehler C et al (2015) Plasticity of an ultrafast interaction between nucleoporins and nuclear transport receptors. Cell 163(3):734–745
Mitchell SF, Parker R (2014) Principles and properties of eukaryotic mRNPs. Mol Cell 54(4):547–558
Mori K, Arzberger T, Grässer FA, Gijselinck I, May S, Rentzsch K et al (2013) Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 126(6):881–893
Murakami K, Tsai K-L, Kalisman N, Bushnell DA, Asturias FJ, Kornberg RD (2015) Structure of an RNA polymerase II preinitiation complex. Proc Natl Acad Sci U S A 112(44):13543–13548
Mühlbauer D, Dzieciolowski J, Hardt M, Hocke A, Schierhorn KL, Mostafa A et al (2015) Influenza virus-induced caspase-dependent enlargement of nuclear pores promotes nuclear export of viral ribonucleoprotein complexes. J Virol 89(11):6009–6021
Müller-McNicoll M, Botti V, de Jesus Domingues AM, Brandl H, Schwich OD, Steiner MC et al (2016) SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export. Genes Dev 30(5):553–566
Nousiainen HO, Kestilä M, Pakkasjärvi N, Honkala H, Kuure S, Tallila J et al (2008) Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet 40(2):155–157
Orr HT, Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575–621
Proudfoot NJ (2011) Ending the message: poly(A) signals then and now. Genes Dev 25(17):1770–1782
Ramaswami M, Taylor JP, Parker R (2013) Altered ribostasis: RNA-protein granules in degenerative disorders. Cell 154(4):727–736
Saito Y, Kasamatsu A, Yamamoto A, Shimizu T, Yokoe H, Sakamoto Y et al (2013) ALY as a potential contributor to metastasis in human oral squamous cell carcinoma. J Cancer Res Clin Oncol 139(4):585–594
Schmidt M, Finley D (2014) Regulation of proteasome activity in health and disease. Biochim Biophys Acta 1843(1):13–25
Schneider M, Hellerschmied D, Schubert T, Amlacher S, Vinayachandran V, Reja R et al (2015) The nuclear pore-associated TREX-2 complex employs mediator to regulate gene expression. Cell 162(5):1016–1028
Sofola OA, Jin P, Qin Y, Duan R, Liu H, de Haro M et al (2007) RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron 55(4):565–571
Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136(4):731–745
Speese SD, Ashley J, Jokhi V, Nunnari J, Barria R, Li Y et al (2012) Nuclear envelope budding enables large ribonucleoprotein particle export during synaptic Wnt signaling. Cell 149(4):832–846
Strässer K, Masuda S, Mason P, Pfannstiel J, Oppizzi M, RodrÃguez-Navarro S et al (2002) TREX is a conserved complex coupling transcription with messenger RNA export. Nature 417(6886):304–308
Stutz F, Bachi A, Doerks T, Braun IC, Séraphin B, Wilm M et al (2000) REF, an evolutionarily conserved family of hnRNP-like proteins, interacts with TAP/Mex67p and participates in mRNA nuclear export. RNA 6(4):638–650
Sun X, Li PP, Zhu S, Cohen R, Marque LO, Ross CA et al (2015) Nuclear retention of full-length HTT RNA is mediated by splicing factors MBNL1 and U2AF65. Sci Rep 5:12521
Svejstrup JQ (2013) RNA polymerase II transcript elongation. Biochim Biophys Acta 1829(1):1
Takai H, Masuda K, Sato T, Sakaguchi Y, Suzuki T, Suzuki T et al (2014) 5-Hydroxymethylcytosine plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex. Cell Rep 9(1):48–60
Taniguchi I, Ohno M (2008) ATP-dependent recruitment of export factor Aly/REF onto intronless mRNAs by RNA helicase UAP56. Mol Cell Biol 28(2):601–608
Todd PK, Oh SY, Krans A, He F, Sellier C, Frazer M et al (2013) CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 78(3):440–455
Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y et al (2015) Differential toxicity of nuclear RNA foci versus dipeptide repeat proteins in a drosophila model of C9ORF72 FTD/ALS. Neuron 87(6):1207–1214
Trcek T, Sato H, Singer RH, Maquat LE (2013) Temporal and spatial characterization of nonsense-mediated mRNA decay. Genes Dev 27(5):541–551
Tsoi H, Lau CK, Lau KF, Chan HYE (2011) Perturbation of U2AF65/NXF1-mediated RNA nuclear export enhances RNA toxicity in polyQ diseases. Hum Mol Genet 20(19):3787–3797
Umlauf D, Bonnet J, Waharte F, Fournier M, Stierle M, Fischer B et al (2013) The human TREX-2 complex is stably associated with the nuclear pore basket. J Cell Sci 126(Pt 12):2656–2667
van der Watt PJ, Maske CP, Hendricks DT, Parker MI, Denny L, Govender D et al (2009) The Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation. Int J Cancer 124(8):1829–1840
Viphakone N, Cumberbatch MG, Livingstone MJ, Heath PR, Dickman MJ, Catto JW et al (2015) Luzp4 defines a new mRNA export pathway in cancer cells. Nucleic Acids Res 43(4):2353–2366
Viphakone N, Hautbergue GM, Walsh M, Chang C-T, Holland A, Folco EG et al (2012) TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export. Nat Commun 3:1006
Walsh MJ, Cooper-Knock J, Dodd JE, Stopford MJ, Mihaylov SR, Kirby J et al (2015) Invited review: decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art. Neuropathol Appl Neurobiol 41(2):109–134
Walsh MJ, Hautbergue GM, Wilson SA (2010) Structure and function of mRNA export adaptors. Biochem Soc Trans 38(Pt 1):232–236
Wickramasinghe VO, Laskey RA (2015) Control of mammalian gene expression by selective mRNA export. Nat Rev Mol Cell Biol 16(7):431–442
Wickramasinghe VO, McMurtrie PIA, Mills AD, Takei Y, Penrhyn-Lowe S, Amagase Y et al (2010) mRNA export from mammalian cell nuclei is dependent on GANP. Curr Biol 20(1):25–31
Wickramasinghe VO, Savill JM, Chavali S, Jonsdottir AB, Rajendra E, Grüner T et al (2013) Human inositol polyphosphate multikinase regulates transcript-selective nuclear mRNA export to preserve genome integrity. Mol Cell 51(6):737–750
Wickramasinghe VO, Venkitaraman AR (2016) RNA processing and genome stability: cause and consequence. Mol Cell 61(4):496–505
Wilson RC, Doudna JA (2013) Molecular mechanisms of RNA interference. Annu Rev Biophys 42:217–239
Wurth L (2012) Versatility of RNA-binding proteins in cancer. Comp Funct Genomics 2012:178525
Xu S, Powers MA (2009) Nuclear pore proteins and cancer. Semin Cell Dev Biol 20(5):620–630
Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD et al (2011) Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A 108(1):260–265
Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J et al (2013) RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A 110(51):E4968–E4977
Acknowledgments
G.M.H. acknowledges support from the Motor Neurone Disease Association (grant Apr16/846-791), the Medical Research Council (MRC grant MR/M010864/1) and the Thierry Latran Foundation (grant FTLAAP2016/Astrocyte secretome).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 American Association of Pharmaceutical Scientists
About this chapter
Cite this chapter
Hautbergue, G.M. (2017). RNA Nuclear Export: From Neurological Disorders to Cancer. In: El-Khamisy, S. (eds) Personalised Medicine. Advances in Experimental Medicine and Biology, vol 1007. Springer, Cham. https://doi.org/10.1007/978-3-319-60733-7_6
Download citation
DOI: https://doi.org/10.1007/978-3-319-60733-7_6
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-60731-3
Online ISBN: 978-3-319-60733-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)