{{Short description|Multi-protein complex}} The '''TREX''' (<u>TR</u>anscription-<u>EX</u>port) '''complex''' is a conserved eukaryotic multi-protein complex that couples mRNA transcription and nuclear export.<ref name="Katahira-2012">{{Cite journal |last=Katahira |first=Jun |date=2012 |title=mRNA export and the TREX complex |journal=Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms |volume=1819 |issue=6 |pages=507–513 |doi=10.1016/j.bbagrm.2011.12.001 |issn=0006-3002 |pmid=22178508|doi-access=free }}</ref> The TREX complex travels across transcribed genes with RNA polymerase II.<ref name="Strässer-2002">{{Cite journal |last1=Strässer |first1=Katja |last2=Masuda |first2=Seiji |last3=Mason |first3=Paul |last4=Pfannstiel |first4=Jens |last5=Oppizzi |first5=Marisa |last6=Rodriguez-Navarro |first6=Susana |last7=Rondón |first7=Ana G. |last8=Aguilera |first8=Andres |last9=Struhl |first9=Kevin |last10=Reed |first10=Robin |last11=Hurt |first11=Ed |date=2002-05-16 |title=TREX is a conserved complex coupling transcription with messenger RNA export |journal=Nature |volume=417 |issue=6886 |pages=304–308 |doi=10.1038/nature746 |issn=0028-0836 |pmid=11979277 |bibcode=2002Natur.417..304S |s2cid=1112194}}</ref> TREX binds mRNA and recruits transport proteins NXF1 and NXT1 (yeast Mex67 and Mtr2), which shuttle the mRNA out of the nucleus.<ref>{{Cite journal |last1=Strässer |first1=K. |last2=Hurt |first2=E. |date=2001-10-11 |title=Splicing factor Sub2p is required for nuclear mRNA export through its interaction with Yra1p |journal=Nature |volume=413 |issue=6856 |pages=648–652 |doi=10.1038/35098113 |issn=0028-0836 |pmid=11675790 |bibcode=2001Natur.413..648S |s2cid=4361359}}</ref><ref name="Köhler-2007">{{Cite journal |last1=Köhler |first1=Alwin |last2=Hurt |first2=Ed |date=2007 |title=Exporting RNA from the nucleus to the cytoplasm |journal=Nature Reviews. Molecular Cell Biology |volume=8 |issue=10 |pages=761–773 |doi=10.1038/nrm2255 |issn=1471-0080 |pmid=17786152 |s2cid=10836137}}</ref><ref name="Hautbergue-2008">{{Cite journal |last1=Hautbergue |first1=Guillaume M. |last2=Hung |first2=Ming-Lung |last3=Golovanov |first3=Alexander P. |last4=Lian |first4=Lu-Yun |last5=Wilson |first5=Stuart A. |date=2008 |title=Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP |journal=Proceedings of the National Academy of Sciences |language=en |volume=105 |issue=13 |pages=5154–5159 |doi=10.1073/pnas.0709167105 |issn=0027-8424 |pmc=2278192 |pmid=18364396 |bibcode=2008PNAS..105.5154H |doi-access=free}}</ref><ref name="Taniguchi-2008">{{Cite journal |last1=Taniguchi |first1=Ichiro |last2=Ohno |first2=Mutsuhito |date=2008 |title=ATP-dependent recruitment of export factor Aly/REF onto intronless mRNAs by RNA helicase UAP56 |journal=Molecular and Cellular Biology |volume=28 |issue=2 |pages=601–608 |doi=10.1128/MCB.01341-07 |issn=1098-5549 |pmc=2223434 |pmid=17984224}}</ref> The TREX complex plays an important role in genome stability and neurodegenerative diseases.<ref name="Heath-2016" />
== Role in mRNA nuclear export == thumb|550x550px|Nuclear export of mRNAs facilitated by TREX complex.<ref name="Katahira-2012" /> During transcription elongation, the THO complex follows RNA polymerase II and interacts with transcription factors along the entire transcribed region.<ref name="Katahira-2012" /> Then, the carboxy-terminal domain (CTD) of RNA polymerase II recruits the 3'-end processing factors/transcription termination factors, which load DEAD-box RNA helicase UAP56 and RNA export adapter ALYREF. This forms the complete TREX complex. At the end of transcription, after the 3'-end of mRNA is formed and the mRNA is released from transcription site, the mRNA is transferred from UAP56 to ALYREF. UAP56 then dissociates, allowing the heterodimeric export receptor NXF1-NXT1 to bind as it recognizes the mRNA indirectly through ALYREF. Further arrangements of mRNA result in ALYREF's release. Finally, the NXF1-NXT1 dimer facilitates mRNA nuclear transport to the cytoplasm through direct interaction with the nuclear pore complex.{{Citation needed|date=December 2022}}
== Composition and conservation in eukaryotic species ==
=== THO complex === thumb|Crystal structure of the THO complex (blue) bound to Sub2 (grey). PDB: 5suq<ref name="Ren-2017">{{Cite journal |last1=Ren |first1=Yi |last2=Schmiege |first2=Philip |last3=Blobel |first3=Günter |date=2017-01-06 |editor-last=Weis |editor-first=Karsten |title=Structural and biochemical analyses of the DEAD-box ATPase Sub2 in association with THO or Yra1 |journal=eLife |volume=6 |article-number=e20070 |doi=10.7554/eLife.20070 |pmid=28059701 |pmc=5218534 |issn=2050-084X |doi-access=free }}</ref>|412x412px The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7. Four of them have counterparts in ''Saccharomyces cerevisiae'': THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1).<ref name="Heath-2016">{{Cite journal |last1=Heath |first1=Catherine G. |last2=Viphakone |first2=Nicolas |last3=Wilson |first3=Stuart A. |date=2016-10-01 |title=The role of TREX in gene expression and disease |url=https://portlandpress.com/biochemj/article/473/19/2911/49675/The-role-of-TREX-in-gene-expression-and-disease |journal=Biochemical Journal |language=en |volume=473 |issue=19 |pages=2911–2935 |doi=10.1042/BCJ20160010 |issn=0264-6021 |pmc=5095910 |pmid=27679854}}</ref><ref>{{Cite journal |last1=Mitchell |first1=Alex L |last2=Attwood |first2=Teresa K |last3=Babbitt |first3=Patricia C |last4=Blum |first4=Matthias |last5=Bork |first5=Peer |last6=Bridge |first6=Alan |last7=Brown |first7=Shoshana D |last8=Chang |first8=Hsin-Yu |last9=El-Gebali |first9=Sara |last10=Fraser |first10=Matthew I |last11=Gough |first11=Julian |last12=Haft |first12=David R |last13=Huang |first13=Hongzhan |last14=Letunic |first14=Ivica |last15=Lopez |first15=Rodrigo |date=2018-11-06 |title=InterPro in 2019: improving coverage, classification and access to protein sequence annotations |journal=Nucleic Acids Research |volume=47 |issue=D1 |pages=D351–D360 |doi=10.1093/nar/gky1100 |issn=0305-1048 |pmc=6323941 |pmid=30398656}}</ref> THOC1 is the first protein identified in THO complex. THOC2 is the largest subunit of TREX. It acts as a scaffold for the formation of the complex. The C-terminal domain of THOC2 directly interacts with nucleic acids. Mutational variants of THOC2 have been associated with syndromic intellectual disabilities, causing seizures, tremors, speech delays, and more.<ref>{{Cite journal |last1=Peña |first1=Álvaro |last2=Gewartowski |first2=Kamil |last3=Mroczek |first3=Seweryn |last4=Cuéllar |first4=Jorge |last5=Szykowska |first5=Aleksandra |last6=Prokop |first6=Andrzej |last7=Czarnocki-Cieciura |first7=Mariusz |last8=Piwowarski |first8=Jan |last9=Tous |first9=Cristina |last10=Aguilera |first10=Andrés |last11=Carrascosa |first11=José L |last12=Valpuesta |first12=José María |last13=Dziembowski |first13=Andrzej |date=2012-03-21 |title=Architecture and nucleic acids recognition mechanism of the THO complex, an mRNP assembly factor: Structure and function of the THO complex |journal=The EMBO Journal |language=en |volume=31 |issue=6 |pages=1605–1616 |doi=10.1038/emboj.2012.10 |pmc=3321177 |pmid=22314234}}</ref><ref>{{Cite journal |last1=Kumar |first1=Raman |last2=Corbett |first2=Mark A. |last3=van Bon |first3=Bregje W. M. |last4=Woenig |first4=Joshua A. |last5=Weir |first5=Lloyd |last6=Douglas |first6=Evelyn |last7=Friend |first7=Kathryn L. |last8=Gardner |first8=Alison |last9=Shaw |first9=Marie |last10=Jolly |first10=Lachlan A. |last11=Tan |first11=Chuan |last12=Hunter |first12=Matthew F. |last13=Hackett |first13=Anna |last14=Field |first14=Michael |last15=Palmer |first15=Elizabeth E. |date=2015-08-06 |title=THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability |journal=American Journal of Human Genetics |volume=97 |issue=2 |pages=302–310 |doi=10.1016/j.ajhg.2015.05.021 |issn=1537-6605 |pmc=4573269 |pmid=26166480}}</ref> THOC 3 and 6 both contains WD40 repeat motifs that allow interaction with other THO proteins.<ref>{{Cite journal |last1=Masuda |first1=Seiji |last2=Das |first2=Rita |last3=Cheng |first3=Hong |last4=Hurt |first4=Ed |last5=Dorman |first5=Nijsje |last6=Reed |first6=Robin |date=2005-07-01 |title=Recruitment of the human TREX complex to mRNA during splicing |journal=Genes & Development |volume=19 |issue=13 |pages=1512–1517 |doi=10.1101/gad.1302205 |issn=0890-9369 |pmc=1172058 |pmid=15998806}}</ref> THOC5 and THOC7 binds tightly and forms a dimer at their coiled coil domain (CCD). Four THO complexes form a tetramer, and each THO complex binds with one UAP56 protein at THOC2 and THOC1.{{Citation needed|date=December 2022}}
=== DDX39/UAP56 === DDX39, or U2AF65-associated protein 56 (UAP56, Sub2 in yeast) is a DEAD-box ATPase essential for pre-mRNA splicing,<ref>{{Cite journal |last1=Fleckner |first1=J. |last2=Zhang |first2=M. |last3=Valcárcel |first3=J. |last4=Green |first4=M. R. |date=1997-07-15 |title=U2AF65 recruits a novel human DEAD box protein required for the U2 snRNP-branchpoint interaction. |url=http://genesdev.cshlp.org/content/11/14/1864 |journal=Genes & Development |language=en |volume=11 |issue=14 |pages=1864–1872 |doi=10.1101/gad.11.14.1864 |issn=0890-9369 |pmid=9242493|s2cid=28531804 |doi-access=free }}</ref> but is also a key component of the TREX complex. DDX39 is very similar to UAP56, sharing 90% of the amino acid sequence.<ref name="Katahira-2012" /> UAP56 travels along genes with the THO complex, where it interacts with the sugar-phosphate backbone of the mRNA.<ref>{{Cite journal |last1=Linder |first1=Patrick |last2=Jankowsky |first2=Eckhard |date=2011 |title=From unwinding to clamping — the DEAD box RNA helicase family |url=http://www.nature.com/articles/nrm3154 |journal=Nature Reviews Molecular Cell Biology |language=en |volume=12 |issue=8 |pages=505–516 |doi=10.1038/nrm3154 |pmid=21779027 |s2cid=2037710 |issn=1471-0072|url-access=subscription }}</ref> UAP56 functions to recruit ALYREF, an RNA export adaptor, to the spliced or intronless mRNA.<ref>{{Cite journal |last1=Luo |first1=M. L. |last2=Zhou |first2=Z. |last3=Magni |first3=K. |last4=Christoforides |first4=C. |last5=Rappsilber |first5=J. |last6=Mann |first6=M. |last7=Reed |first7=R. |year=2001 |title=Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly |journal=Nature |volume=413 |issue=6856 |pages=644–647 |doi=10.1038/35098106|pmid=11675789 |bibcode=2001Natur.413..644L |s2cid=4395388 }}</ref><ref name="Taniguchi-2008" /> After transfer of the mRNA from UAP56 to ALYREF, UAP56 dissociates from the complex, allowing the binding of export factor NXF1 to ALYREF at the same site.<ref name="Kiesler-2002">{{Cite journal |last1=Kiesler |first1=Eva |last2=Miralles |first2=Francesc |last3=Visa |first3=Neus |date=2002-05-14 |title=HEL/UAP56 Binds Cotranscriptionally to the Balbiani Ring Pre-mRNA in an Intron-Independent Manner and Accompanies the BR mRNP to the Nuclear Pore |journal=Current Biology |language=English |volume=12 |issue=10 |pages=859–862 |doi=10.1016/S0960-9822(02)00840-0 |pmid=12015125 |s2cid=17926674 |issn=0960-9822|doi-access=free }}</ref><ref name="Köhler-2007" /> thumb|486x486px|Crystal Structure of Sub2 (grey) and Yra1 (purple) complexed with mRNA (orange). PDB: 5sup<ref name="Ren-2017" /> {{#invoke:Infobox_gene|getTemplateData|QID=Q18032666}}
==== DDX39a ==== In mammalian cells, a paralog of DDX39b, DDX39a, exists, and is somewhat functionally redundant. Knockdown of both paralogs is required to block mRNA export,<ref name="Hautbergue-2009">{{Cite journal |last1=Hautbergue |first1=Guillaume M. |last2=Hung |first2=Ming-Lung |last3=Walsh |first3=Matthew J. |last4=Snijders |first4=Ambrosius P.L. |last5=Chang |first5=Chung-Te |last6=Jones |first6=Rachel |last7=Ponting |first7=Chris P. |last8=Dickman |first8=Mark J. |last9=Wilson |first9=Stuart A. |date=2009 |title=UIF, a New mRNA Export Adaptor that Works Together with REF/ALY, Requires FACT for Recruitment to mRNA |journal=Current Biology |language=en |volume=19 |issue=22 |pages=1918–1924 |doi=10.1016/j.cub.2009.09.041 |pmc=2828547 |pmid=19836239}}</ref><ref>{{Cite journal |last=Pryor |first=A. |date=2004-03-26 |title=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 |journal=Nucleic Acids Research |language=en |volume=32 |issue=6 |pages=1857–1865 |doi=10.1093/nar/gkh347 |issn=1362-4962 |pmc=390356 |pmid=15047853}}</ref> but depletion of either paralog affects different forms of mRNAs.<ref>{{Cite journal |last1=Yamazaki |first1=Tomohiro |last2=Fujiwara |first2=Naoko |last3=Yukinaga |first3=Hiroko |last4=Ebisuya |first4=Miki |last5=Shiki |first5=Takuya |last6=Kurihara |first6=Tomoya |last7=Kioka |first7=Noriyuki |last8=Kambe |first8=Taiho |last9=Nagao |first9=Masaya |last10=Nishida |first10=Eisuke |last11=Masuda |first11=Seiji |date=2010-08-15 |editor-last=Weis |editor-first=Karsten |title=The Closely Related RNA helicases, UAP56 and URH49, Preferentially Form Distinct mRNA Export Machineries and Coordinately Regulate Mitotic Progression |journal=Molecular Biology of the Cell |language=en |volume=21 |issue=16 |pages=2953–2965 |doi=10.1091/mbc.e09-10-0913 |issn=1059-1524 |pmc=2921121 |pmid=20573985}}</ref> DDX39b is shown to associate with THO and ALYREF, and DDX39a with CIP29 and ALYREF.<ref name="Yamazaki-2010">{{Cite journal |title=The Closely Related RNA helicases, UAP56 and URH49, Preferentially Form Distinct mRNA Export Machineries and Coordinately Regulate Mitotic Progression |year=2010 |language=en |doi=10.1091/mbc.e09-10-0913 |pmc=2921121 |pmid=20573985|last1=Yamazaki |first1=Tomohiro |last2=Fujiwara |first2=Naoko |last3=Yukinaga |first3=Hiroko |last4=Ebisuya |first4=Miki |last5=Shiki |first5=Takuya |last6=Kurihara |first6=Tomoya |last7=Kioka |first7=Noriyuki |last8=Kambe |first8=Taiho |last9=Nagao |first9=Masaya |last10=Nishida |first10=Eisuke |last11=Masuda |first11=Seiji |journal=Molecular Biology of the Cell |volume=21 |issue=16 |pages=2953–2965 }}</ref>
=== ALYREF === ALYREF (Yra1 in yeast) is an essential RNA export adapter involved in the export of both spliced and intronless mRNAs.<ref>{{Cite journal |last1=Rodrigues |first1=João P. |last2=Rode |first2=Michaela |last3=Gatfield |first3=David |last4=Blencowe |first4=Benjamin J. |last5=Carmo-Fonseca |first5=Maria |last6=Izaurralde |first6=Elisa |date=2001-01-30 |title=REF proteins mediate the export of spliced and unspliced mRNAs from the nucleus |journal=Proceedings of the National Academy of Sciences |language=en |volume=98 |issue=3 |pages=1030–1035 |doi=10.1073/pnas.98.3.1030 |pmid=11158589 |pmc=14703 |bibcode=2001PNAS...98.1030R |issn=0027-8424|doi-access=free }}</ref> The N and C-termini of ALYREF both contain UAP56-bonding motifs (UBMs), which are necessary for its interaction with UAP56.<ref name="Hautbergue-2009" /> ALYREF also contains an RNA recognition motif (RRM) that weakly binds RNA,<ref>{{Cite journal |last1=Golovanov |first1=Alexander P. |last2=Hautbergue |first2=Guillaume M. |last3=Tintaru |first3=Aura M. |last4=Lian |first4=Lu-Yun |last5=Wilson |first5=Stuart A. |date=2006-11-01 |title=The solution structure of REF2-I reveals interdomain interactions and regions involved in binding mRNA export factors and RNA |url=http://rnajournal.cshlp.org/content/12/11/1933 |journal=RNA |language=en |volume=12 |issue=11 |pages=1933–1948 |doi=10.1261/rna.212106 |issn=1355-8382 |pmc=1624900 |pmid=17000901}}</ref> and is flanked by two arginine-rich RNA binding sites. ALYREF alone cannot bind mRNA effectively, and requires interaction with UAP56 to bind the mRNA in the TREX Complex (see Figure 3). These arginine-rich sites are also necessary for ALYREF's interaction with export receptor NXF1, which stimulates the transfer of the mRNA from ALYREF to NXF1.<ref name="Hautbergue-2008" /> Like UAP56, ALYREF dissociates prior to nuclear export of the mRNA.<ref name="Kiesler-2002" /><ref>{{Cite journal |last=Kim |first=V.N. |date=2001-04-17 |title=The Y14 protein communicates to the cytoplasm the position of exon-exon junctions |url=http://emboj.embopress.org/cgi/doi/10.1093/emboj/20.8.2062 |journal=The EMBO Journal |volume=20 |issue=8 |pages=2062–2068 |doi=10.1093/emboj/20.8.2062 |pmc=125236 |pmid=11296238}}</ref> The unstructured and flexible nature of ALYREF indicates it may play a key role in packaging the mRNA and proteins into a messenger ribonuclear protein (mRNP) for nuclear export.<ref>{{Cite journal |last1=Björk |first1=Petra |last2=Wieslander |first2=Lars |date=2015-06-02 |title=The Balbiani Ring Story: Synthesis, Assembly, Processing, and Transport of Specific Messenger RNA–Protein Complexes |journal=Annual Review of Biochemistry |language=en |volume=84 |issue=1 |pages=65–92 |doi=10.1146/annurev-biochem-060614-034150 |pmid=26034888 |issn=0066-4154|doi-access=free }}</ref>
==== UIF/FYTTD1 ==== UIF, identified through gene homology of ALYREF's UAP56-binding domain, is functionally redundant with ALYREF. Knockdown of ALYREF in mammalian cells results in large upregulation of UIF. UIF can associate with the other TREX complex components in an RNA-independent manner.<ref name="Hautbergue-2009" /> UIF is speculated to associate with alternative TREX complexes in place of ALYREF, perhaps acting on certain types or mRNAs.{{Citation needed|date=December 2022}}
=== CHTOP === Originally identified as a RNA-binding protein involved in cell cycle regulation,<ref>{{Cite journal |last1=Zullo |first1=Alfred J. |last2=Michaud |first2=Monia |last3=Zhang |first3=Weiping |last4=Grusby |first4=Michael J. |date=2009 |title=Identification of the Small Protein Rich in Arginine and Glycine (SRAG) |journal=Journal of Biological Chemistry |language=en |volume=284 |issue=18 |pages=12504–12511 |doi=10.1074/jbc.M809436200 |pmc=2673316 |pmid=19254951|doi-access=free }}</ref> CHTOP contains two UBMs like those in ALYREF and UIF, and is thought to function in a similar manner to ALYREF. CHTOP has also been shown to stimulate UAP56 ATPase activity.<ref name="ReferenceA">{{Cite journal |last1=Chang |first1=Chung-Te |last2=Hautbergue |first2=Guillaume M |last3=Walsh |first3=Matthew J |last4=Viphakone |first4=Nicolas |last5=van Dijk |first5=Thamar B |last6=Philipsen |first6=Sjaak |last7=Wilson |first7=Stuart A |date=2013-01-08 |title=Chtop is a component of the dynamic TREX mRNA export complex |journal=The EMBO Journal |volume=32 |issue=3 |pages=473–486 |doi=10.1038/emboj.2012.342 |issn=0261-4189 |pmc=3567497 |pmid=23299939}}</ref> CHTOP is speculated to associate with alternative TREX complexes in place of UAP56, perhaps acting on specific types or mRNAs.{{Citation needed|date=December 2022}}
=== SARNP/CIP29 === SARNP/CIP29 (yeast Tho1), identified alongside yeast Tho2,<ref>{{Cite journal |last=Piruat |first=J. I. |date=1998-08-17 |title=A novel yeast gene, THO2, is involved in RNA pol II transcription and provides new evidence for transcriptional elongation-associated recombination |url=http://emboj.embopress.org/cgi/doi/10.1093/emboj/17.16.4859 |journal=The EMBO Journal |volume=17 |issue=16 |pages=4859–4872 |doi=10.1093/emboj/17.16.4859 |pmc=1170815 |pmid=9707445}}</ref> forms a trimeric complex with UAP56 and ALYREF,<ref>{{Cite journal |last1=Dufu |first1=Kobina |last2=Livingstone |first2=Michaela J. |last3=Seebacher |first3=Jan |last4=Gygi |first4=Steven P. |last5=Wilson |first5=Stuart A. |last6=Reed |first6=Robin |date=2010-09-15 |title=ATP is required for interactions between UAP56 and two conserved mRNA export proteins, Aly and CIP29, to assemble the TREX complex |journal=Genes & Development |language=en |volume=24 |issue=18 |pages=2043–2053 |doi=10.1101/gad.1898610 |issn=0890-9369 |pmc=2939366 |pmid=20844015}}</ref> and has been shown to preferentially associate with DDX39a.<ref name="Yamazaki-2010" /> SARNP stimulates UAP56 ATPase activity.<ref name="ReferenceA"/><ref>{{Cite journal |last1=Sugiura |first1=Takeyuki |last2=Sakurai |first2=Kayo |last3=Nagano |first3=Yuki |date=2007 |title=Intracellular characterization of DDX39, a novel growth-associated RNA helicase |url=https://linkinghub.elsevier.com/retrieve/pii/S0014482706004861 |journal=Experimental Cell Research |language=en |volume=313 |issue=4 |pages=782–790 |doi=10.1016/j.yexcr.2006.11.014|pmid=17196963 |url-access=subscription }}</ref> {| class="wikitable sortable" |+Conservation of the TREX Complex ! !Yeast !''Drosophila'' !Mammals |- | rowspan="7" |THO components |Hpr1 |Thoc1 |Thoc1 (hHpr1) |- |Tho2 |Thoc2 |Thoc2 |- |Thp2 | | |- |Mft1 |Thoc7 |Thoc7 |- | |Thoc5 |Thoc5 (FMIP) |- | |Thoc6 |Thoc6 |- |Tex1 |Thoc3 |Thoc3 (hTEX1) |- | rowspan="2" |DEAD-box type helicase |Sub2 |Uap56 |Uap56 |- | | |DDX39 |- |Adaptor mRNA binding protein |Yra1 |Aly |ALYREF |}
== Associated proteins ==
=== NXF1 === NXF1(Mex67p in yeast), also known as nuclear RNA export factor 1, is a multi-domain protein composed of one conserved N-terminal RNA recognition and four leucine-rich repeat motifs, a central NTF2-like domain, and a C-terminal ubiquitin associated domain that mediates interactions with nucleoporins. The NTF2-like domain is able to form heterodimers with NTF2-related export protein-1 (NXT1). The heterodimer binds mRNAs processed by the TREX complex and assists the TREX complex in the nuclear export process.<ref>{{Cite journal |last=Segref |first=A. |date=1997-06-01 |title=Mex67p, a novel factor for nuclear mRNA export, binds to both poly(A)+ RNA and nuclear pores |journal=The EMBO Journal |volume=16 |issue=11 |pages=3256–3271 |doi=10.1093/emboj/16.11.3256 |pmid=9214641 |pmc=1169942 |issn=1460-2075}}</ref><ref>{{Cite journal |last1=Teplova |first1=Marianna |last2=Wohlbold |first2=Lara |last3=Khin |first3=Nyan W |last4=Izaurralde |first4=Elisa |last5=Patel |first5=Dinshaw J |date=2011 |title=Structure-function studies of nucleocytoplasmic transport of retroviral genomic RNA by mRNA export factor TAP |journal=Nature Structural & Molecular Biology |language=en |volume=18 |issue=9 |pages=990–998 |doi=10.1038/nsmb.2094 |issn=1545-9993 |pmc=3167930 |pmid=21822283}}</ref>
=== NXT1 === NXT1 (Mtr2p in yeast) is also known as p15. It shuttles between the nucleus and the cytoplasm acting as an active nuclear transport protein. NXT1 binds specifically to Ran-GTP and localizes to the nuclear pore complex in mammalian cells. It also stabilizes and forms heterodimers with NXF1. The heterodimer binds mRNAs processed by the TREX complex and assists the TREX complex in the nuclear export process.<ref>{{Cite journal |last1=Black |first1=Ben E. |last2=Lévesque |first2=Lyne |last3=Holaska |first3=James M. |last4=Wood |first4=Todd C. |last5=Paschal |first5=Bryce M. |date=1999 |title=Identification of an NTF2-Related Factor That Binds Ran-GTP and Regulates Nuclear Protein Export |journal=Molecular and Cellular Biology |volume=19 |issue=12 |pages=8616–8624 |doi=10.1128/mcb.19.12.8616 |pmid=10567585 |pmc=84993 |issn=0270-7306}}</ref>
=== NCBP1 & NCBP3 === NCBP1 and NCBP3 are both part of the cap-binding complex. The two proteins interact with each other as well as the TREX complex in facilitating the mRNA export from the nucleus to the cytoplasm. NCBP3 further interact with exon junction complex proteins for mRNA splicing and stability.<ref>{{Cite journal |last1=Gebhardt |first1=Anna |last2=Habjan |first2=Matthias |last3=Benda |first3=Christian |last4=Meiler |first4=Arno |last5=Haas |first5=Darya A. |last6=Hein |first6=Marco Y. |last7=Mann |first7=Angelika |last8=Mann |first8=Matthias |last9=Habermann |first9=Bianca |last10=Pichlmair |first10=Andreas |date=2015 |title=mRNA export through an additional cap-binding complex consisting of NCBP1 and NCBP3 |journal=Nature Communications |language=en |volume=6 |issue=1 |page=8192 |doi=10.1038/ncomms9192 |issn=2041-1723 |pmc=4595607 |pmid=26382858|bibcode=2015NatCo...6.8192G }}</ref>
== Role in genome stability, mutations, and diseases == The TREX complex is a conserved protein complex that couples transcription to mRNA export and is linked to genome stability and several disorders.
=== Genome stability === The TREX complex plays an important role in genome stability. Newly formed RNA strands can hybridize with the single-stranded template DNA sequence during transcription, leading to an R-loop.<ref name="Heath-2016" /> The R-loop makes the opposing DNA strand more susceptible to cleavage, which can cause DNA damage in cells.<ref name="Heath-2016" /> The TREX complex associates with the RNA polymerase and newly formed RNA, sequestering the RNA and, therefore, preventing its hybridization to the DNA strand, improving genome stability.<ref name="Heath-2016" />
=== Neurodegenerative diseases === The TREX complex is associated with several neurodegenerative and neurodevelopmental disorders. These disorders are caused by mutations in the TREX complex itself or in other genes.<ref name="Heath-2016" />
==== Direct mutations in TREX subunits ==== Several mutations in the THOC2 gene, part of the THO complex, are associated with disease. For example, missense mutations, or a change in a nucleotide that results in the encoding of a different amino acid, in this gene and translocations on the X chromosome are associated with intellectual disabilities.<ref name="Heath-2016" /><ref>{{Cite web |title=Missense Mutation |url=https://www.genome.gov/genetics-glossary/Missense-Mutation |access-date=2022-10-24 |website=Genome.gov |language=en}}</ref>
The THOC6 gene, part of the THO complex, plays a role in the development of the brain and other organs. Mutations on this gene leads to the incorrect localization of the protein in the cytoplasm, an essential process for neural and organ development.<ref name="Heath-2016" /> A homozygous mutation in this gene can lead to not only intellectual disability, but cardiac defects and brain malformation.<ref name="Heath-2016" />
==== Mutations in other genes ==== Mutations in other genes can also have an indirect dependence on the TREX complex and lead to disease, including familial amyotrophic lateral sclerosis(ALS). ALS is a rare neurodegenerative disease that leads to the death of motor neurons in the brain, resulting in the loss of voluntary movement.<ref>{{Cite web |title=What is ALS? |url=https://www.als.org/understanding-als/what-is-als |access-date=2022-10-25 |website=The ALS Association |language=en}}</ref> In the familial form of the disease, a GGGGCC repeat in an intron of the C9ORF72 gene is expanded in the pre-mRNA, which is exported to the cytoplasm and forms RNA foci.<ref name="Heath-2016" /> ALYREF binds to the repeat expansion, and an excess recruitment promotes its export.<ref name="Heath-2016" /> A mutation that disrupts its activity suppresses neurodegeneration, and is enhanced by CHTOP and NXF1.<ref name="Heath-2016" />
== See also == * THOC1 * THOC2 * THOC5 * BAT1 * DDX39 * ALYREF * SARNP * NXT1 * NXF1
== References == {{Reflist}}