Skip to main content

Mechanism and Regulation of Co-transcriptional mRNP Assembly and Nuclear mRNA Export

Part of the Advances in Experimental Medicine and Biology book series (AEMB,volume 1203)

Abstract

mRNA is the “hermes” of gene expression as it carries the information of a protein-coding gene to the ribosome. Already during its synthesis, the mRNA is bound by mRNA-binding proteins that package the mRNA into a messenger ribonucleoprotein particle (mRNP). This mRNP assembly is important for mRNA stability and nuclear mRNA export. It also often regulates later steps in the mRNA lifetime such as translation and mRNA degradation in the cytoplasm. Thus, mRNP composition and accordingly the assembly of nuclear mRNA-binding proteins onto the mRNA are of crucial importance for correct gene expression. Here, we review our current knowledge of the mechanism of co-transcriptional mRNP assembly and nuclear mRNA export. We introduce the proteins involved and elaborate on what is known about their functions so far. In addition, we discuss the importance of regulated mRNP assembly in changing environmental conditions, especially during stress. Furthermore, we examine how defects in mRNP assembly cause diseases and how viruses exploit the host’s nuclear mRNA export pathway. Finally, we summarize the questions that need to be answered in the future.

Keywords

  • mRNA
  • RNA-binding protein
  • RBP
  • mRNA assembly
  • mRNP
  • Nuclear mRNA export

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

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Abruzzi KC, Lacadie S, Rosbash M (2004) Biochemical analysis of TREX complex recruitment to intronless and intron-containing yeast genes. EMBO J 23:2620–2631

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Adams RL, Mason AC, Glass L, Aditi, Wente SR (2017) Nup42 and IP6 coordinate Gle1 stimulation of Dbp5/DDX19B for mRNA export in yeast and human cells. Traffic 18:776–790

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Adivarahan S, Livingston N, Nicholson B, Rahman S, Wu B, Rissland OS, Zenklusen D (2018) Spatial organization of single mRNPs at different stages of the gene expression pathway. Mol Cell 72:727–738 e725

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Aguilera A, Garcia-Muse T (2012) R loops: from transcription byproducts to threats to genome stability. Mol Cell 46:115–124

    CrossRef  CAS  PubMed  Google Scholar 

  • Aibara S, Gordon JM, Riesterer AS, McLaughlin SH, Stewart M (2017) Structural basis for the dimerization of Nab2 generated by RNA binding provides insight into its contribution to both poly(A) tail length determination and transcript compaction in Saccharomyces cerevisiae. Nucleic Acids Res 45:1529–1538

    CrossRef  CAS  PubMed  Google Scholar 

  • Alcazar-Roman AR, Tran EJ, Guo SL, Wente SR (2006) Inositol hexakisphosphate and Gle1 activate the DEAD-box protein Dbp5 for nuclear mRNA export. Nat Cell Biol 8:711–U131

    CrossRef  CAS  PubMed  Google Scholar 

  • Amos JS, Huang L, Thevenon J, Kariminedjad A, Beaulieu CL, Masurel-Paulet A, Najmabadi H, Fattahi Z, Beheshtian M, Tonekaboni SH et al (2017) Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping. Clin Genet 91:92–99

    CrossRef  CAS  PubMed  Google Scholar 

  • Anderson JT, Wilson SM, Datar KV, Swanson MS (1993) NAB2: a yeast nuclear polyadenylated RNA-binding protein essential for cell viability. Mol Cell Biol 13:2730–2741

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Aravind L, Koonin EV (1999) G-patch: a new conserved domain in eukaryotic RNA-processing proteins and type D retroviral polyproteins. Trends Biochem Sci 24:342–344

    CrossRef  CAS  PubMed  Google Scholar 

  • Bachi A, Braun IC, Rodrigues JP, Pante N, Ribbeck K, von Kobbe C, Kutay U, Wilm M, Gorlich D, Carmo-Fonseca M et al (2000) 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

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Baejen C, Torkler P, Gressel S, Essig K, Soding J, Cramer P (2014) Transcriptome maps of mRNP biogenesis factors define pre-mRNA recognition. Mol Cell 55:745–757

    CrossRef  CAS  PubMed  Google Scholar 

  • Balasubramaniam VR, Hong Wai T, Ario Tejo B, Omar AR, Syed Hassan S (2013) Highly pathogenic avian influenza virus nucleoprotein interacts with TREX complex adaptor protein Aly/REF. PLoS One 8:e72429

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Batisse J, Batisse C, Budd A, Bottcher B, Hurt E (2009) Purification of nuclear poly(A)-binding protein Nab2 reveals association with the yeast transcriptome and a messenger ribonucleoprotein core structure. J Biol Chem 284:34911–34917

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Beaulieu CL, Huang L, Innes AM, Akimenko MA, Puffenberger EG, Schwartz C, Jerry P, Ober C, Hegele RA, McLeod DR et al (2013) Intellectual disability associated with a homozygous missense mutation in THOC6. Orphanet J Rare Dis 8:62

    CrossRef  PubMed  PubMed Central  Google Scholar 

  • Beckmann BM, Castello A, Medenbach J (2016) The expanding universe of ribonucleoproteins: of novel RNA-binding proteins and unconventional interactions. Pflugers Arch: Eur J Physiol 468:1029–1040

    CrossRef  CAS  Google Scholar 

  • Bhatia V, Barroso SI, Garcia-Rubio ML, Tumini E, Herrera-Moyano E, Aguilera A (2014) BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature 511:362–365

    CrossRef  CAS  PubMed  Google Scholar 

  • Bienkowski RS, Banerjee A, Rounds JC, Rha J, Omotade OF, Gross C, Morris KJ, Leung SW, Pak C, Jones SK et al (2017) The conserved, disease-associated RNA binding protein dNab2 interacts with the fragile X protein ortholog in drosophila neurons. Cell Rep 20:1372–1384

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Bjork P, Wieslander L (2015) The Balbiani ring story: synthesis, assembly, processing, and transport of specific messenger RNA-protein complexes. Annu Rev Biochem 84:65–92

    CrossRef  PubMed  CAS  Google Scholar 

  • Bjork P, Wieslander L (2017) Integration of mRNP formation and export. Cell Mol Life Sci 74:2875–2897

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Boehm V, Gehring NH (2016) Exon junction complexes: supervising the gene expression assembly line. Trends Genet 32:724–735

    CrossRef  CAS  PubMed  Google Scholar 

  • Boehringer A, Bowser R (2018) RNA nucleocytoplasmic transport defects in neurodegenerative diseases. Adv Neurobiol 20:85–101

    CrossRef  PubMed  Google Scholar 

  • Boehringer A, Garcia-Mansfield K, Singh G, Bakkar N, Pirrotte P, Bowser R (2017) ALS associated mutations in Matrin 3 alter protein-protein interactions and impede mRNA nuclear export. Sci Rep 7:14529

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Bourgeois CF, Mortreux F, Auboeuf D (2016) The multiple functions of RNA helicases as drivers and regulators of gene expression. Nat Rev Mol Cell Biol 17:426–438

    CrossRef  CAS  PubMed  Google Scholar 

  • Brown SJ, Stoilov P, Xing Y (2012) Chromatin and epigenetic regulation of pre-mRNA processing. Hum Mol Genet 21:R90–R96

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Bucheli ME, Buratowski S (2005) Npl3 is an antagonist of mRNA 3′ end formation by RNA polymerase II. EMBO J 24:2150–2160

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Buratowski S (2009) Progression through the RNA polymerase II CTD cycle. Mol Cell 36:541–546

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Carey KT, Wickramasinghe VO (2018) Regulatory potential of the RNA processing machinery: implications for human disease. Trends Genet 34:279–290

    CrossRef  CAS  PubMed  Google Scholar 

  • Carmody SR, Tran EJ, Apponi LH, Corbett AH, Wente SR (2010) The mitogen-activated protein kinase Slt2 regulates nuclear retention of non-heat shock mRNAs during heat shock-induced stress. Mol Cell Biol 30:5168–5179

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Castellano-Pozo M, Santos-Pereira JM, Rondon AG, Barroso S, Andujar E, Perez-Alegre M, Garcia-Muse T, Aguilera A (2013) R loops are linked to histone H3 S10 phosphorylation and chromatin condensation. Mol Cell 52:583–590

    CrossRef  CAS  PubMed  Google Scholar 

  • Chanarat S, Strasser K (2013) Splicing and beyond: the many faces of the Prp19 complex. Biochim Biophys Acta 1833:2126–2134

    CrossRef  CAS  PubMed  Google Scholar 

  • Chanarat S, Seizl M, Strasser K (2011) The Prp19 complex is a novel transcription elongation factor required for TREX occupancy at transcribed genes. Genes Dev 25:1147–1158

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Chanarat S, Burkert-Kautzsch C, Meinel DM, Strasser K (2012) Prp19C and TREX: interacting to promote transcription elongation and mRNA export. Transcription 3:8–12

    CrossRef  PubMed  Google Scholar 

  • Chang CT, Hautbergue GM, Walsh MJ, Viphakone N, van Dijk TB, Philipsen S, Wilson SA (2013) Chtop is a component of the dynamic TREX mRNA export complex. EMBO J 32:473–486

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng H, Dufu K, Lee CS, Hsu JL, Dias A, Reed R (2006) Human mRNA export machinery recruited to the 5′ end of mRNA. Cell 127:1389–1400

    CrossRef  CAS  PubMed  Google Scholar 

  • Chi B, Wang Q, Wu G, Tan M, Wang L, Shi M, Chang X, Cheng H (2013) 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

    CrossRef  CAS  PubMed  Google Scholar 

  • Chi BK, Wang K, Du YH, Gui B, Chang XY, Wang LT, Fan J, Chen S, Wu XD, Li GH et al (2014) A sub-element in PRE enhances nuclear export of intronless mRNAs by recruiting the TREX complex via ZC3H18. Nucleic Acids Res 42:7305–7318

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiba S, Hill-Batorski L, Neumann G, Kawaoka Y (2018) The cellular DExD/H-Box RNA helicase UAP56 Co-localizes with the influenza A virus NS1 protein. Front Microbiol 9:2192

    CrossRef  PubMed  PubMed Central  Google Scholar 

  • Chinnam M, Wang Y, Zhang X, Gold DL, Khoury T, Nikitin AY, Foster BA, Li Y, Bshara W, Morrison CD et al (2014) The Thoc1 ribonucleoprotein and prostate cancer progression. J Natl Cancer Inst 106

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Cloutier SC, Ma WK, Nguyen LT, Tran EJ (2012) The DEAD-box RNA helicase Dbp2 connects RNA quality control with repression of aberrant transcription. J Biol Chem 287:26155–26166

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Cooper-Knock J, Walsh MJ, Higginbottom A, Robin Highley J, Dickman MJ, Edbauer D, Ince PG, Wharton SB, Wilson SA, Kirby J et al (2014) Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137:2040–2051

    CrossRef  PubMed  PubMed Central  Google Scholar 

  • Corbett AH (2018) Post-transcriptional regulation of gene expression and human disease. Curr Opin Cell Biol 52:96–104

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Dargemont C, Babour A (2017) Novel functions for chromatin dynamics in mRNA biogenesis beyond transcription. Nucleus (Austin, Tex.) 8:482–488

    CAS  Google Scholar 

  • Delaleau M, Borden KL (2015) Multiple export mechanisms for mRNAs. Cell 4:452–473

    CrossRef  CAS  Google Scholar 

  • Dermody JL, Dreyfuss JM, Villen J, Ogundipe B, Gygi SP, Park PJ, Ponticelli AS, Moore CL, Buratowski S, Bucheli ME (2008) Unphosphorylated SR-like protein Npl3 stimulates RNA polymerase II elongation. PLoS One 3:e3273

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Di Gregorio E, Bianchi FT, Schiavi A, Chiotto AM, Rolando M, Verdun di Cantogno L, Grosso E, Cavalieri S, Calcia A, Lacerenza D 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 50:543–551

    CrossRef  PubMed  CAS  Google Scholar 

  • Dominguez-Sanchez MS, Barroso S, Gomez-Gonzalez B, Luna R, Aguilera A (2011a) Genome instability and transcription elongation impairment in human cells depleted of THO/TREX. PLoS Genet 7:e1002386

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Dominguez-Sanchez MS, Saez C, Japon MA, Aguilera A, Luna R (2011b) Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers. BMC Cancer 11:77

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 24:2043–2053

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Dutta S, Gupta G, Choi YW, Kotaka M, Fielding BC, Song J, Tan YJ (2012) The variable N-terminal region of DDX5 contains structural elements and auto-inhibits its interaction with NS5B of hepatitis C virus. Biochem J 446:37–46

    CrossRef  CAS  PubMed  Google Scholar 

  • Fasken MB, Corbett AH (2016) Links between mRNA splicing, mRNA quality control, and intellectual disability. RNA Dis 3:e1448

    PubMed  PubMed Central  Google Scholar 

  • Ficner R, Dickmanns A, Neumann P (2017) Studying structure and function of spliceosomal helicases. Methods 125:63–69

    CrossRef  CAS  PubMed  Google Scholar 

  • Fischer T, Strasser K, Racz A, Rodriguez-Navarro S, Oppizzi M, Ihrig P, Lechner J, Hurt E (2002) 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

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Fleckner J, Zhang M, Valcarcel J, Green MR (1997) U2AF(65) recruits a novel human DEAD box protein required for the U2 snRNP-branchpoint interaction. Genes Dev 11:1864–1872

    CrossRef  CAS  PubMed  Google Scholar 

  • Folco EG, Lee CS, Dufu K, Yamazaki T, Reed R (2012) 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

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC et al (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525:129–133

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujimura S, Xing Y, Takeya M, Yamashita Y, Ohshima K, Kuwahara K, Sakaguchi N (2005) Increased expression of germinal center-associated nuclear protein RNA-primase is associated with lymphomagenesis. Cancer Res 65:5925–5934

    CrossRef  CAS  PubMed  Google Scholar 

  • Fukuda S, Wu DW, Stark K, Pelus LM (2002) Cloning and characterization of a proliferation-associated cytokine-inducible protein, CIP29. Biochem Biophys Res Commun 292:593–600

    CrossRef  CAS  PubMed  Google Scholar 

  • Gaillard H, Wellinger RE, Aguilera A (2007) A new connection of mRNP biogenesis and export with transcription-coupled repair. Nucleic Acids Res 35:3893–3906

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Gatfield D, Le Hir H, Schmitt C, Braun IC, Kocher T, Wilm M, Izaurralde E (2001) The DExH/D box protein HEL/UAP56 is essential for mRNA nuclear export in Drosophila. Curr Biol 11:1716–1721

    CrossRef  CAS  PubMed  Google Scholar 

  • Gehring NH, Wahle E, Fischer U (2017) Deciphering the mRNP code: RNA-bound determinants of post-transcriptional gene regulation. Trends Biochem Sci 42:369–382

    CrossRef  CAS  PubMed  Google Scholar 

  • Germain H, Qu N, Cheng YT, Lee E, Huang Y, Dong OX, Gannon P, Huang S, Ding P, Li Y et al (2010) MOS11: a new component in the mRNA export pathway. PLoS Genet 6:e1001250

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilbert W, Guthrie C (2004) The Glc7p nuclear phosphatase promotes mRNA export by facilitating association of Mex67p with mRNA. Mol Cell 13:201–212

    CrossRef  CAS  PubMed  Google Scholar 

  • Gilbert W, Siebel CW, Guthrie C (2001) Phosphorylation by Sky1p promotes Npl3p shuttling and mRNA dissociation. RNA 7:302–313

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomez-Gonzalez B, Garcia-Rubio M, Bermejo R, Gaillard H, Shirahige K, Marin A, Foiani M, Aguilera A (2011) Genome-wide function of THO/TREX in active genes prevents R-loop-dependent replication obstacles. EMBO J 30:3106–3119

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonatopoulos-Pournatzis T, Cowling VH (2014) Cap-binding complex (CBC). Biochem J 457:231–242

    CrossRef  CAS  PubMed  Google Scholar 

  • Gorbalenya AE, Koonin EV (1993) Helicases - amino-acid-sequence comparisons and structure-function-relationships. Curr Opin Struct Biol 3:419–429

    CrossRef  CAS  Google Scholar 

  • Green DM, Marfatia KA, Crafton EB, Zhang X, Cheng X, Corbett AH (2002) Nab2p is required for poly(A) RNA export in Saccharomyces cerevisiae and is regulated by arginine methylation via Hmt1p. J Biol Chem 277:7752–7760

    CrossRef  CAS  PubMed  Google Scholar 

  • Griaud F, Pierce A, Gonzalez Sanchez MB, Scott M, Abraham SA, Holyoake TL, Tran DD, Tamura T, Whetton AD (2013) A pathway from leukemogenic oncogenes and stem cell chemokines to RNA processing via THOC5. Leukemia 27:932–940

    CrossRef  CAS  PubMed  Google Scholar 

  • Gromadzka AM, Steckelberg AL, Singh KK, Hofmann K, Gehring NH (2016) A short conserved motif in ALYREF directs cap- and EJC-dependent assembly of export complexes on spliced mRNAs. Nucleic Acids Res 44:2348–2361

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Gruter P, Tabernero C, von Kobbe C, Schmitt C, Saavedra C, Bachi A, Wilm M, Felber BK, Izaurralde E (1998) TAP, the human homolog of Mex67p, mediates CTE-dependent RNA export from the nucleus. Mol Cell 1:649–659

    CrossRef  CAS  PubMed  Google Scholar 

  • Guo S, Hakimi MA, Baillat D, Chen X, Farber MJ, Klein-Szanto AJ, Cooch NS, Godwin AK, Shiekhattar R (2005) Linking transcriptional elongation and messenger RNA export to metastatic breast cancers. Cancer Res 65:3011–3016

    CrossRef  CAS  PubMed  Google Scholar 

  • Guo S, Liu M, Godwin AK (2012) Transcriptional regulation of hTREX84 in human cancer cells. PLoS One 7:e43610

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Gwizdek C, Iglesias N, Rodriguez MS, Ossareh-Nazari B, Hobeika M, Divita G, Stutz F, Dargemont C (2006) Ubiquitin-associated domain of Mex67 synchronizes recruitment of the mRNA export machinery with transcription. Proc Natl Acad Sci U S A 103:16376–16381

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Harlen KM, Churchman LS (2017) The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain. Nat Rev Mol Cell Biol 18:263–273

    CrossRef  CAS  PubMed  Google Scholar 

  • Hashii Y, Kim JY, Sawada A, Tokimasa S, Hiroyuki F, Ohta H, Makiko K, Takihara Y, Ozono K, Hara J (2004) A novel partner gene CIP29 containing a SAP domain with MLL identified in infantile myelomonocytic leukemia. Leukemia 18:1546–1548

    CrossRef  CAS  PubMed  Google Scholar 

  • Hautbergue GM, Hung ML, Golovanov AP, Lian LY, Wilson SA (2008) Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP. Proc Natl Acad Sci U S A 105:5154–5159

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Hautbergue GM, Hung ML, Walsh MJ, Snijders AP, Chang CT, Jones R, Ponting CP, Dickman MJ, Wilson SA (2009) UIF, a new mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA. Curr Biol 19:1918–1924

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Hautbergue GM, Castelli LM, Ferraiuolo L, Sanchez-Martinez A, Cooper-Knock J, Higginbottom A, Lin Y-H, Bauer CS, Dodd JE, Myszczynska MA et al (2017) SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nat Commun 8:16063

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Heath CG, Viphakone N, Wilson SA (2016) The role of TREX in gene expression and disease. Biochem J 473:2911–2935

    CrossRef  CAS  PubMed  Google Scholar 

  • Hector RE, Nykamp KR, Dheur S, Anderson JT, Non PJ, Urbinati CR, Wilson SM, Minvielle-Sebastia L, Swanson MS (2002) Dual requirement for yeast hnRNP Nab2p in mRNA poly(A) tail length control and nuclear export. EMBO J 21:1800–1810

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Heidemann M, Hintermair C, Voss K, Eick D (2012) Dynamic phosphorylation patterns of RNA polymerase II CTD during transcription. Biochim Biophys Acta 1829:55–62

    CrossRef  PubMed  CAS  Google Scholar 

  • Hentze MW, Castello A, Schwarzl T, Preiss T (2018) A brave new world of RNA-binding proteins. Nat Rev Mol Cell Biol 19:327–341

    CrossRef  CAS  PubMed  Google Scholar 

  • Hiriart E, Bardouillet L, Manet E, Gruffat H, Penin F, Montserret R, Farjot G, Sergeant A (2003) A region of the Epstein-Barr virus (EBV) mRNA export factor EB2 containing an arginine-rich motif mediates direct binding to RNA. J Biol Chem 278:37790–37798

    CrossRef  CAS  PubMed  Google Scholar 

  • Hirling H, Scheffner M, Restle T, Stahl H (1989) RNA helicase activity associated with the human p68 protein. Nature 339:562–564

    CrossRef  CAS  PubMed  Google Scholar 

  • Hodge CA, Tran EJ, Noble KN, Alcazar-Roman AR, Ben-Yishay R, Scarcelli JJ, Folkmann AW, Shav-Tal Y, Wente SR, Cole CN (2011) 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

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsin JP, Manley JL (2012) The RNA polymerase II CTD coordinates transcription and RNA processing. Genes Dev 26:2119–2137

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu Y, Gor V, Morikawa K, Nagata K, Kawaguchi A (2017) Cellular splicing factor UAP56 stimulates trimeric NP formation for assembly of functional influenza viral ribonucleoprotein complexes. Sci Rep 7:14053

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Huang Y, Gattoni R, Stevenin J, Steitz JA (2003) SR splicing factors serve as adapter proteins for TAP-dependent mRNA export. Mol Cell 11:837–843

    CrossRef  CAS  PubMed  Google Scholar 

  • Huertas P, Aguilera A (2003) Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol Cell 12:711–721

    CrossRef  CAS  PubMed  Google Scholar 

  • Hurt E, Luo MJ, Rother S, Reed R, Strasser K (2004) Cotranscriptional recruitment of the serine-arginine-rich (SR)-like proteins Gbp2 and Hrb1 to nascent mRNA via the TREX complex. Proc Natl Acad Sci U S A 101:1858–1862

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Hurt JA, Obar RA, Zhai B, Farny NG, Gygi SP, Silver PA (2009) A conserved CCCH-type zinc finger protein regulates mRNA nuclear adenylation and export. J Cell Biol 185:265–277

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Iglesias N, Tutucci E, Gwizdek C, Vinciguerra P, Von Dach E, Corbett AH, Dargemont C, Stutz F (2010) Ubiquitin-mediated mRNP dynamics and surveillance prior to budding yeast mRNA export. Genes Dev 24:1927–1938

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackson BR, Noerenberg M, Whitehouse A (2014) A novel mechanism inducing genome instability in Kaposi’s sarcoma-associated herpesvirus infected cells. PLoS Pathog 10:e1004098

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Jankowsky E, Harris ME (2015) Specificity and nonspecificity in RNA-protein interactions. Nat Rev Mol Cell Biol 16:533–544

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Jankowsky A, Guenther U-P, Jankowsky E (2011) The RNA helicase database. Nucleic Acids Res 39:D338–D341

    CrossRef  CAS  PubMed  Google Scholar 

  • Jensen TH, Boulay J, Rosbash M, Libri D (2001) The DECD box putative ATPase Sub2p is an early mRNA export factor. Curr Biol 11:1711–1715

    CrossRef  CAS  PubMed  Google Scholar 

  • Jeronimo C, Bataille AR, Robert F (2013) The writers, readers, and functions of the RNA polymerase II C-terminal domain code. Chem Rev 113:8491–8522

    CrossRef  CAS  PubMed  Google Scholar 

  • Jeronimo C, Collin P, Robert F (2016) The RNA polymerase II CTD: the increasing complexity of a low-complexity protein domain. J Mol Biol 428:2607–2622

    CrossRef  CAS  PubMed  Google Scholar 

  • Jimeno S, Luna R, Garcia-Rubio M, Aguilera A (2006) Tho1, a novel hnRNP, and Sub2 provide alternative pathways for mRNP biogenesis in yeast THO mutants. Mol Cell Biol 26:4387–4398

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson SA, Cubberley G, Bentley DL (2009) Cotranscriptional recruitment of the mRNA export factor Yra1 by direct interaction with the 3′ end processing factor Pcf11. Mol Cell 33:215–226

    CrossRef  CAS  PubMed  Google Scholar 

  • Kelly SM, Leung SW, Pak C, Banerjee A, Moberg KH, Corbett AH (2014) A conserved role for the zinc finger polyadenosine RNA binding protein, ZC3H14, in control of poly(A) tail length. RNA 20:681–688

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelly SM, Bienkowski R, Banerjee A, Melicharek DJ, Brewer ZA, Marenda DR, Corbett AH, Moberg KH (2015) The Drosophila ortholog of the Zc3h14 RNA binding protein acts within neurons to pattern axon projection in the developing brain. Dev Neurobiol. 76:93–106

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Kistler AL, Guthrie C (2001) Deletion of MUD2, the yeast homolog of U2AF65, can bypass the requirement for sub2, an essential spliceosomal ATPase. Genes Dev 15:42–49

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Kohler A, Hurt E (2007) Exporting RNA from the nucleus to the cytoplasm. Nat Rev Mol Cell Biol 8:761–773

    CrossRef  PubMed  CAS  Google Scholar 

  • Kota KP, Wagner SR, Huerta E, Underwood JM, Nickerson JA (2008) Binding of ATP to UAP56 is necessary for mRNA export. J Cell Sci 121:1526–1537

    CrossRef  CAS  PubMed  Google Scholar 

  • Kress TL, Krogan NJ, Guthrie C (2008) A single SR-like protein, Npl3, promotes pre-mRNA splicing in budding yeast. Mol Cell 32:727–734

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Kubitscheck U, Siebrasse JP (2017) Kinetics of transport through the nuclear pore complex. Semin Cell Dev Biol 68:18–26

    CrossRef  CAS  PubMed  Google Scholar 

  • Kumar R, Corbett MA, van Bon BW, Woenig JA, Weir L, Douglas E, Friend KL, Gardner A, Shaw M, Jolly LA et al (2015) THOC2 mutations implicate mRNA-export pathway in X-linked intellectual disability. Am J Hum Genet 97:302–310

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar R, Gardner A, Homan CC, Douglas E, Mefford H, Wieczorek D, Ludecke HJ, Stark Z, Sadedin S, Broad CMG et al (2018) Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery. Hum Mutat 39:1126–1138

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuss SK, Mata MA, Zhang L, Fontoura BM (2013) Nuclear imprisonment: viral strategies to arrest host mRNA nuclear export. Viruses 5:1824–1849

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Lai MC, Tarn WY (2004) Hypophosphorylated ASF/SF2 binds TAP and is present in messenger ribonucleoproteins. J Biol Chem 279:31745–31749

    CrossRef  CAS  PubMed  Google Scholar 

  • Lapek JD Jr, Greninger P, Morris R, Amzallag A, Pruteanu-Malinici I, Benes CH, Haas W (2017) Detection of dysregulated protein-association networks by high-throughput proteomics predicts cancer vulnerabilities. Nat Biotechnol 35:983

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee MS, Henry M, Silver PA (1996) A protein that shuttles between the nucleus and the cytoplasm is an important mediator of RNA export. Genes Dev 10:1233–1246

    CrossRef  CAS  PubMed  Google Scholar 

  • Lei EP, Krebber H, Silver PA (2001) Messenger RNAs are recruited for nuclear export during transcription. Genes Dev 15:1771–1782

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Lei H, Dias AP, Reed R (2011) Export and stability of naturally intronless mRNAs require specific coding region sequences and the TREX mRNA export complex. Proc Natl Acad Sci U S A 108:17985–17990

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Lei H, Zhai B, Yin S, Gygi S, Reed R (2013) Evidence that a consensus element found in naturally intronless mRNAs promotes mRNA export. Nucleic Acids Res 41:2517–2525

    CrossRef  CAS  PubMed  Google Scholar 

  • Li Y, Wang X, Zhang X, Goodrich DW (2005) Human hHpr1/p84/Thoc1 regulates transcriptional elongation and physically links RNA polymerase II and RNA processing factors. Mol Cell Biol 25:4023–4033

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 67:6657–6664

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin DH, Correia AR, Cai SW, Huber FM, Jette CA, Hoelz A (2018) Structural and functional analysis of mRNA export regulation by the nuclear pore complex. Nat Commun 9:2319

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Linder P, Jankowsky E (2011) From unwinding to clamping – the DEAD box RNA helicase family. Nat Rev Mol Cell Biol 12:505–516

    CrossRef  CAS  PubMed  Google Scholar 

  • Linder P, Stutz F (2001) mRNA export: travelling with DEAD box proteins. Curr Biol 11:R961–R963

    CrossRef  CAS  PubMed  Google Scholar 

  • Linder P, Lasko PF, Ashburner M, Leroy P, Nielsen PJ, Nishi K, Schnier J, Slonimski PP (1989) Birth of the D-E-A-D box. Nature 337:121–122

    CrossRef  CAS  PubMed  Google Scholar 

  • Lischka P, Toth Z, Thomas M, Mueller R, Stamminger T (2006) The UL69 transactivator protein of human cytomegalovirus interacts with DEXD/H-Box RNA helicase UAP56 to promote cytoplasmic accumulation of unspliced RNA. Mol Cell Biol 26:1631–1643

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu C, Yue B, Yuan C, Zhao S, Fang C, Yu Y, Yan D (2015) Elevated expression of Thoc1 is associated with aggressive phenotype and poor prognosis in colorectal cancer. Biochem Biophys Res Commun 468:53–58

    CrossRef  CAS  PubMed  Google Scholar 

  • Luco RF, Pan Q, Tominaga K, Blencowe BJ, Pereira-Smith OM, Misteli T (2010) Regulation of alternative splicing by histone modifications. Science 327:996–1000

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo MJ, Zhou ZL, Magni K, Christoforides C, Rappsilber J, Mann M, Reed R (2001) Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 413:644–647

    CrossRef  CAS  PubMed  Google Scholar 

  • Ma WK, Cloutier SC, Tran EJ (2013) The DEAD-box protein Dbp2 functions with the RNA-binding protein Yra1 to promote mRNP assembly. J Mol Biol 425:3824–3838

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma WK, Paudel BP, Xing Z, Sabath IG, Rueda D, Tran EJ (2016) Recruitment, duplex unwinding and protein-mediated inhibition of the dead-box RNA helicase Dbp2 at actively transcribed chromatin. J Mol Biol 428:1091–1106

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • MacMorris M, Brocker C, Blumenthal T (2003) UAP56 levels affect viability and mRNA export in Caenorhabditis elegans. RNA 9:847–857

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Maeder CI, Kim JI, Liang X, Kaganovsky K, Shen A, Li Q, Li Z, Wang S, Xu XZS, Li JB et al (2018) The THO complex coordinates transcripts for synapse development and dopamine neuron survival. Cell 174:1436–1449.e1420

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 19:1512–1517

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Meignin C, Davis I (2008) UAP56 RNA helicase is required for axis specification and cytoplasmic mRNA localization in Drosophila. Dev Biol 315:89–98

    CrossRef  CAS  PubMed  Google Scholar 

  • Meinel DM, Strasser K (2015) Co-transcriptional mRNP formation is coordinated within a molecular mRNP packaging station in S. cerevisiae. Bioessays 37:666–677

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Meinel DM, Burkert-Kautzsch C, Kieser A, O'Duibhir E, Siebert M, Mayer A, Cramer P, Soding J, Holstege FC, Strasser K (2013) Recruitment of TREX to the transcription machinery by its direct binding to the phospho-CTD of RNA polymerase II. PLoS Genet 9:e1003914

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Metkar M, Ozadam H, Lajoie BR, Imakaev M, Mirny LA, Dekker J, Moore MJ (2018) Higher-order organization principles of pre-translational mRNPs. Mol Cell 72:715–726.e713

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Montpetit B, Thomsen ND, Helmke KJ, Seeliger MA, Berger JM, Weis K (2011) A conserved mechanism of DEAD-box ATPase activation by nucleoporins and InsP6 in mRNA export. Nature 472:238–242

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Moukhtar M, Chaar W, Abdel-Razzak Z, Khalil M, Taha S, Chamieh H (2017) ARCPHdb: a comprehensive protein database for SF1 and SF2 helicase from archaea. Comput Biol Med 80:185–189

    CrossRef  CAS  PubMed  Google Scholar 

  • Muller-McNicoll M, Botti V, de Jesus Domingues AM, Brandl H, Schwich OD, Steiner MC, Curk T, Poser I, Zarnack K, Neugebauer KM (2016) SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export. Genes Dev 30:553–566

    CrossRef  PubMed  PubMed Central  Google Scholar 

  • Nino CA, Herissant L, Babour A, Dargemont C (2013) mRNA nuclear export in yeast. Chem Rev 113:8523–8545

    CrossRef  CAS  PubMed  Google Scholar 

  • Noble SM, Guthrie C (1996) Transcriptional pulse-chase analysis reveals a role for a novel snRNP-associated protein in the manufacture of spliceosomal snRNPs. EMBO J 15:4368–4379

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Noble KN, Tran EJ, Alcazar-Roman AR, Hodge CA, Cole CN, Wente SR (2011) 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

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Nojima T, Hirose T, Kimura H, Hagiwara M (2007) The interaction between cap-binding complex and RNA export factor is required for intronless mRNA export. J Biol Chem 282:15645–15651

    CrossRef  CAS  PubMed  Google Scholar 

  • Nojima T, Gomes T, Grosso ARF, Kimura H, Dye MJ, Dhir S, Carmo-Fonseca M, Proudfoot NJ (2015) Mammalian NET-seq reveals genome-wide nascent transcription coupled to RNA processing. Cell 161:526–540

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Ote I, Lebrun M, Vandevenne P, Bontems S, Medina-Palazon C, Manet E, Piette J, Sadzot-Delvaux C (2009) Varicella-zoster virus IE4 protein interacts with SR proteins and exports mRNAs through the TAP/NXF1 pathway. PLoS One 4:e7882

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Pryor A, Tung L, Yang Z, Kapadia F, Chang TH, Johnson LF (2004) Growth-regulated expression and G0-specific turnover of the mRNA that encodes URH49, a mammalian DExH/D box protein that is highly related to the mRNA export protein UAP56. Nucleic Acids Res 32:1857–1865

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Putnam AA, Jankowsky E (2013) DEAD-box helicases as integrators of RNA, nucleotide and protein binding. BBA-Gene Regul Mech 1829:884–893

    CAS  Google Scholar 

  • Ren Y, Schmiege P, Blobel G (2017) Structural and biochemical analyses of the DEAD-box ATPase Sub2 in association with THO or Yra1. Elife 6

    Google Scholar 

  • Reuter LM, Meinel DM, Strasser K (2015) The poly(A)-binding protein Nab2 functions in RNA polymerase III transcription. Genes Dev 29:1565–1575

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Riordan DP, Herschlag D, Brown PO (2011) Identification of RNA recognition elements in the Saccharomyces cerevisiae transcriptome. Nucleic Acids Res 39:1501–1509

    CrossRef  CAS  PubMed  Google Scholar 

  • Rodriguez-Navarro S, Fischer T, Luo MJ, Antunez O, Brettschneider S, Lechner J, Perez-Ortin JE, Reed R, Hurt E (2004) Sus1, a functional component of the SAGA histone acetylase complex and the nuclear pore-associated mRNA export machinery. Cell 116:75–86

    CrossRef  CAS  PubMed  Google Scholar 

  • Rudolph MG, Klostermeier D (2015) When core competence is not enough: functional interplay of the DEAD-box helicase core with ancillary domains and auxiliary factors in RNA binding and unwinding. Biol Chem 396:849–865

    CrossRef  CAS  PubMed  Google Scholar 

  • Saguez C, Gonzales FA, Schmid M, Boggild A, Latrick CM, Malagon F, Putnam A, Sanderson L, Jankowsky E, Brodersen DE et al (2013) Mutational analysis of the yeast RNA helicase Sub2p reveals conserved domains required for growth, mRNA export, and genomic stability. RNA 19:1363–1371

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Saito Y, Kasamatsu A, Yamamoto A, Shimizu T, Yokoe H, Sakamoto Y, Ogawara K, Shiiba M, Tanzawa H, Uzawa K (2013) ALY as a potential contributor to metastasis in human oral squamous cell carcinoma. J Cancer Res Clin Oncol 139:585–594

    CrossRef  CAS  PubMed  Google Scholar 

  • Sakaguchi N, Maeda K (2016) Germinal center B-cell-associated nuclear protein (GANP) involved in RNA metabolism for B cell maturation. In: Alt FW (ed) Advances in immunology. Academic, New York, pp 135–186

    Google Scholar 

  • Salas-Armenteros I, Pérez-Calero C, Bayona-Feliu A, Tumini E, Luna R, Aguilera A (2017) Human THO–Sin3A interaction reveals new mechanisms to prevent R-loops that cause genome instability. EMBO J 36:3532–3547

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Santos-Pereira JM, Aguilera A (2015) R loops: new modulators of genome dynamics and function. Nat Rev Genet 16:583–597

    CrossRef  CAS  PubMed  Google Scholar 

  • Schneider M, Hellerschmied D, Schubert T, Amlacher S, Vinayachandran V, Reja R, Pugh BF, Clausen T, Kohler A (2015) The nuclear pore-associated TREX-2 complex employs mediator to regulate gene expression. Cell 162:1016–1028

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Schubert T, Köhler A (2016) Mediator and TREX-2: emerging links between transcription initiation and mRNA export. Nucleus 7(2):126–131

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Schumann S, Whitehouse A (2017) Targeting the human TREX complex to prevent herpesvirus replication: what is new? Future Virol 12:81–83

    CrossRef  CAS  Google Scholar 

  • Schumann S, Baquero-Perez B, Whitehouse A (2016a) Interactions between KSHV ORF57 and the novel human TREX proteins, CHTOP and CIP29. J Gen Virol 97:1904–1910

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Schumann S, Jackson BR, Yule I, Whitehead SK, Revill C, Foster R, Whitehouse A (2016b) Targeting the ATP-dependent formation of herpesvirus ribonucleoprotein particle assembly as an antiviral approach. Nat Microbiol 2:16201

    CrossRef  CAS  PubMed  Google Scholar 

  • Schutz P, Karlberg T, van den Berg S, Collins R, Lehtio L, Hogbom M, Holmberg-Schiavone L, Tempel W, Park HW, Hammarstrom M et al (2010) Comparative structural analysis of human DEAD-box RNA helicases. PLoS One 5:e12791

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Segref A, Sharma K, Doye V, Hellwig A, Huber J, Luhrmann R, Hurt E (1997) Mex67p, a novel factor for nuclear mRNA export, binds to both poly(A)+ RNA and nuclear pores. EMBO J 16:3256–3271

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen JP, Zhang LD, Zhao R (2007) Biochemical characterization of the ATPase and helicase activity of UAP56, an essential pre-mRNA splicing and mRNA export factor. J Biol Chem 282:22544–22550

    CrossRef  CAS  PubMed  Google Scholar 

  • Shi H, Cordin O, Minder CM, Linder P, Xu RM (2004) Crystal structure of the human ATP-dependent splicing and export factor UAP56. Proc Natl Acad Sci U S A 101:17628–17633

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi M, Zhang H, Wu X, He Z, Wang L, Yin S, Tian B, Li G, Cheng H (2017) ALYREF mainly binds to the 5′ and the 3′ regions of the mRNA in vivo. Nucleic Acids Res 45:9640–9653

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Simone R, Balendra R, Moens TG, Preza E, Wilson KM, Heslegrave A, Woodling NS, Niccoli T, Gilbert-Jaramillo J, Abdelkarim S et al (2018) G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. EMBO Mol Med 10:22–31

    CrossRef  CAS  PubMed  Google Scholar 

  • Singh G, Pratt G, Yeo GW, Moore MJ (2015) The clothes make the mRNA: past and present trends in mRNP fashion. Annu Rev Biochem 84:325–354

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Singleton MR, Dillingham MS, Wigley DB (2007) Structure and mechanism of helicases and nucleic acid translocases. Annu Rev Biochem 76:23–50

    CrossRef  CAS  PubMed  Google Scholar 

  • Skoglund U, Andersson K, Strandberg B, Daneholt B (1986) Three-dimensional structure of a specific pre-messenger RNP particle established by electron microscope tomography. Nature 319:560–564

    CrossRef  CAS  PubMed  Google Scholar 

  • Sloan KE, Bohnsack MT (2018) Unravelling the mechanisms of RNA helicase regulation. Trends Biochem Sci 43:237–250

    CrossRef  CAS  PubMed  Google Scholar 

  • Sollier J, Cimprich KA (2015) Breaking bad: R-loops and genome integrity. Trends Cell Biol 25:514–522

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Strahm Y, Fahrenkrog B, Zenklusen D, Rychner E, Kantor J, Rosbash M, Stutz F (1999) The RNA export factor Gle1p is located on the cytoplasmic fibrils of the NPC and physically interacts with the FG-nucleoporin Rip1p, the DEAD-box protein Rat8p/Dbp5p and a new protein Ymr255p. EMBO J 18:5761–5777

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Strasser K, Hurt E (2000) Yra1p, a conserved nuclear RNA-binding protein, interacts directly with Mex67p and is required for mRNA export. EMBO J 19:410–420

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

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

    CrossRef  CAS  PubMed  Google Scholar 

  • Strasser K, Bassler J, Hurt E (2000) Binding of the Mex67p/Mtr2p heterodimer to FXFG, GLFG, and FG repeat nucleoporins is essential for nuclear mRNA export. J Cell Biol 150:695–706

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Strasser K, Masuda S, Mason P, Pfannstiel J, Oppizzi M, Rodriguez-Navarro S, Rondon AG, Aguilera A, Struhl K, Reed R et al (2002) TREX is a conserved complex coupling transcription with messenger RNA export. Nature 417:304–308

    CrossRef  PubMed  CAS  Google Scholar 

  • Stubbs SH, Conrad NK (2015) Depletion of REF/Aly alters gene expression and reduces RNA polymerase II occupancy. Nucleic Acids Res 43:504–519

    CrossRef  CAS  PubMed  Google Scholar 

  • Taniguchi I, Ohno M (2008) ATP-dependent recruitment of export factor Aly/REF onto intronless mRNAs by RNA helicase UAP56. Mol Cell Biol 28:601–608

    CrossRef  CAS  PubMed  Google Scholar 

  • Tieg B, Krebber H (2013) Dbp5 – from nuclear export to translation. Biochim Biophys Acta 1829:791–798

    CrossRef  CAS  PubMed  Google Scholar 

  • Trcek T, Larson DR, Moldon A, Query CC, Singer RH (2011) Single-molecule mRNA decay measurements reveal promoter-regulated mRNA stability in yeast. Cell 147:1484–1497

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Tuck AC, Tollervey D (2013) A transcriptome-wide atlas of RNP composition reveals diverse classes of mRNAs and lncRNAs. Cell 154:996–1009

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Tunnicliffe RB, Hautbergue GM, Kalra P, Jackson BR, Whitehouse A, Wilson SA, Golovanov AP (2011) Structural basis for the recognition of cellular mRNA export factor REF by herpes viral proteins HSV-1 ICP27 and HVS ORF57. PLoS Pathog 7:e1001244

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Tunnicliffe RB, Hautbergue GM, Wilson SA, Kalra P, Golovanov AP (2014) Competitive and cooperative interactions mediate RNA transfer from herpesvirus saimiri ORF57 to the mammalian export adaptor ALYREF. PLoS Pathog 10:e1003907

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Tunnicliffe RB, Tian X, Storer J, Sandri-Goldin RM, Golovanov AP (2018) Overlapping motifs on the herpes viral proteins ICP27 and ORF57 mediate interactions with the mRNA export adaptors ALYREF and UIF. Sci Rep 8:15005

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  • Umlauf D, Bonnet J, Waharte F, Fournier M, Stierle M, Fischer B, Brino L, Devys D, Tora L (2013) The human TREX-2 complex is stably associated with the nuclear pore basket. J Cell Sci 126:2656–2667

    CrossRef  CAS  PubMed  Google Scholar 

  • Valencia P, Dias AP, Reed R (2008) Splicing promotes rapid and efficient mRNA export in mammalian cells. Proc Natl Acad Sci U S A 105:3386–3391

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Viphakone N, Hautbergue GM, Walsh M, Chang CT, Holland A, Folco EG, Reed R, Wilson SA (2012) TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export. Nat Commun 3:1006

    CrossRef  PubMed  CAS  Google Scholar 

  • Viphakone N, Cumberbatch MG, Livingstone MJ, Heath PR, Dickman MJ, Catto JW, Wilson SA (2015) Luzp4 defines a new mRNA export pathway in cancer cells. Nucleic Acids Res 43:2353–2366

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Vitaliano-Prunier A, Babour A, Herissant L, Apponi L, Margaritis T, Holstege FC, Corbett AH, Gwizdek C, Dargemont C (2012) H2B ubiquitylation controls the formation of export-competent mRNP. Mol Cell 45:132–139

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Vohhodina J, Barros EM, Savage AL, Liberante FG, Manti L, Bankhead P, Cosgrove N, Madden AF, Harkin DP, Savage KI (2017) The RNA processing factors THRAP3 and BCLAF1 promote the DNA damage response through selective mRNA splicing and nuclear export. Nucleic Acids Res 45:12816–12833

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Wallace EW, Kear-Scott JL, Pilipenko EV, Schwartz MH, Laskowski PR, Rojek AE, Katanski CD, Riback JA, Dion MF, Franks AM et al (2015) Reversible, specific, active aggregates of endogenous proteins assemble upon heat stress. Cell 162:1286–1298

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Walsh MJ, Cooper-Knock J, Dodd JE, Stopford MJ, Mihaylov SR, Kirby J, Shaw PJ, Hautbergue GM (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 41:109–134

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Weirich CS, Erzberger JP, Flick JS, Berger JM, Thorner J, Weis K (2006) 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

    CrossRef  CAS  PubMed  Google Scholar 

  • Wickramasinghe VO, Laskey RA (2015) Control of mammalian gene expression by selective mRNA export. Nat Rev Mol Cell Biol 16:431–442

    CrossRef  CAS  PubMed  Google Scholar 

  • Wickramasinghe VO, McMurtrie PI, Mills AD, Takei Y, Penrhyn-Lowe S, Amagase Y, Main S, Marr J, Stewart M, Laskey RA (2010) mRNA export from mammalian cell nuclei is dependent on GANP. Curr Biol 20:25–31

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Wickramasinghe VO, Savill JM, Chavali S, Jonsdottir AB, Rajendra E, Gruner T, Laskey RA, Babu MM, Venkitaraman AR (2013) Human inositol polyphosphate multikinase regulates transcript-selective nuclear mRNA export to preserve genome integrity. Mol Cell 51:737–750

    CrossRef  CAS  PubMed  Google Scholar 

  • Wickramasinghe VO, Andrews R, Ellis P, Langford C, Gurdon JB, Stewart M, Venkitaraman AR, Laskey RA (2014) Selective nuclear export of specific classes of mRNA from mammalian nuclei is promoted by GANP. Nucleic Acids Res 42:5059–5071

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Xing Z, Ma WK, Tran EJ (2018) The DDX5/Dbp2 subfamily of DEAD-box RNA helicases. Wiley interdisciplinary reviews. RNA 10:e1519

    PubMed  Google Scholar 

  • Yamazaki T, Fujiwara N, Yukinaga H, Ebisuya M, Shiki T, Kurihara T, Kioka N, Kambe T, Nagao M, Nishida E et al (2010) The closely related RNA helicases, UAP56 and URH49, preferentially form distinct mRNA export machineries and coordinately regulate mitotic progression. Mol Biol Cell 21:2953–2965

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Yarbrough ML, Mata MA, Sakthivel R, Fontoura BMA (2014) Viral subversion of nucleocytoplasmic trafficking. Traffic 15:127–140

    CrossRef  CAS  PubMed  Google Scholar 

  • Yoh SM, Cho H, Pickle L, Evans RM, Jones KA (2007) The Spt6 SH2 domain binds Ser2-P RNAPII to direct Iws1-dependent mRNA splicing and export. Genes Dev 21:160–174

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Younis S, Kamel W, Falkeborn T, Wang H, Yu D, Daniels R, Essand M, Hinkula J, Akusjarvi G, Andersson L (2018) Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth. Proc Natl Acad Sci U S A 115:E3808–E3816

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  • Zaborowska J, Egloff S, Murphy S (2016) The pol II CTD: new twists in the tail. Nat Struct Mol Biol 23:771–777

    CrossRef  CAS  PubMed  Google Scholar 

  • Zander G, Krebber H (2017) Quick or quality? How mRNA escapes nuclear quality control during stress. RNA Biol 14:1–7

    CrossRef  Google Scholar 

  • Zander G, Hackmann A, Bender L, Becker D, Lingner T, Salinas G, Krebber H (2016) mRNA quality control is bypassed for immediate export of stress-responsive transcripts. Nature 540:593

    CrossRef  CAS  PubMed  Google Scholar 

  • Zhao R, Shen J, Green MR, MacMorris M, Blumenthal T (2004) Crystal structure of UAP56, a DExD/H-box protein involved in pre-mRNA splicing and mRNA export. Structure 12:1373–1381

    CrossRef  CAS  PubMed  Google Scholar 

  • Zhou ZL, Luo M, Straesser K, Katahira J, Hurt E, Reed R (2000) The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 407:401–405

    CrossRef  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Katja Sträßer .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Wende, W., Friedhoff, P., Sträßer, K. (2019). Mechanism and Regulation of Co-transcriptional mRNP Assembly and Nuclear mRNA Export. In: Oeffinger, M., Zenklusen, D. (eds) The Biology of mRNA: Structure and Function . Advances in Experimental Medicine and Biology, vol 1203. Springer, Cham. https://doi.org/10.1007/978-3-030-31434-7_1

Download citation