Co-transcriptional pre-mRNA splicing is not obligatory. Pre-mRNA splicing begins co-transcriptionally and often continues post-transcriptionally. Human genes contain an average of nine introns per gene, which cannot serve as splicing substrates until both 5' and 3' ends of each intron are synthesized. Thus the time that it takes for pol II to synthesize each intron defines a minimal time and distance along the gene in which splicing factors can be recruited. The time that it takes for pol II to reach the end of the gene defines the maximal time in which splicing could occur co-transcriptionally. Thus, the kinetics of transcription can affect the kinetics of splicing.Any covalent change in a primary (nascent) mRNA transcript is mRNA Processing. For successful gene expression, the primary mRNA transcript needs to be converted to a mature mRNA prior to its translation into polypeptide. Eucaryotic mRNAs undergo a series of complex processing reactions; these begin on nascent transcripts as soon as a few ribonucleotides have been synthesized during transcription by RNA Polymerase II, through the export of the mature mRNA to the cytoplasm, and culminate with mRNA turnover in the cytoplasm.
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Pathway is converted from Reactome ID: 72203
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Reactome version: 64
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Reactome Author: Carmichael, Gordon G, Hammarskjold, Marie-Louise, Hastings, Michelle L, Krainer, Adrian R, Marzluff, William F, Wahle, Elmar, Zhang, Z
Hutten S, Kehlenbach RH.; ''CRM1-mediated nuclear export: to the pore and beyond.''; PubMedEurope PMCScholia
Lévesque L, Guzik B, Guan T, Coyle J, Black BE, Rekosh D, Hammarskjöld ML, Paschal BM.; ''RNA export mediated by tap involves NXT1-dependent interactions with the nuclear pore complex.''; PubMedEurope PMCScholia
Coltri P, Effenberger K, Chalkley RJ, Burlingame AL, Jurica MS.; ''Breaking up the C complex spliceosome shows stable association of proteins with the lariat intron intermediate.''; PubMedEurope PMCScholia
Zhou Z, Licklider LJ, Gygi SP, Reed R.; ''Comprehensive proteomic analysis of the human spliceosome.''; PubMedEurope PMCScholia
Le Hir H, Izaurralde E, Maquat LE, Moore MJ.; ''The spliceosome deposits multiple proteins 20-24 nucleotides upstream of mRNA exon-exon junctions.''; PubMedEurope PMCScholia
Ma XM, Yoon SO, Richardson CJ, Jülich K, Blenis J.; ''SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs.''; PubMedEurope PMCScholia
Ajuh P, Sleeman J, Chusainow J, Lamond AI.; ''A direct interaction between the carboxyl-terminal region of CDC5L and the WD40 domain of PLRG1 is essential for pre-mRNA splicing.''; PubMedEurope PMCScholia
Hegele A, Kamburov A, Grossmann A, Sourlis C, Wowro S, Weimann M, Will CL, Pena V, Lührmann R, Stelzl U.; ''Dynamic protein-protein interaction wiring of the human spliceosome.''; PubMedEurope PMCScholia
Pikielny CW, Bindereif A, Green MR.; ''In vitro reconstitution of snRNPs: a reconstituted U4/U6 snRNP participates in splicing complex formation.''; PubMedEurope PMCScholia
Kataoka N, Dreyfuss G.; ''A simple whole cell lysate system for in vitro splicing reveals a stepwise assembly of the exon-exon junction complex.''; PubMedEurope PMCScholia
Hung ML, Hautbergue GM, Snijders AP, Dickman MJ, Wilson SA.; ''Arginine methylation of REF/ALY promotes efficient handover of mRNA to TAP/NXF1.''; PubMedEurope PMCScholia
Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ.; ''Proteomic analysis of the mammalian nuclear pore complex.''; PubMedEurope PMCScholia
Suyama M, Doerks T, Braun IC, Sattler M, Izaurralde E, Bork P.; ''Prediction of structural domains of TAP reveals details of its interaction with p15 and nucleoporins.''; PubMedEurope PMCScholia
Grote M, Wolf E, Will CL, Lemm I, Agafonov DE, Schomburg A, Fischle W, Urlaub H, Lührmann R.; ''Molecular architecture of the human Prp19/CDC5L complex.''; PubMedEurope PMCScholia
Moore CL, Sharp PA.; ''Accurate cleavage and polyadenylation of exogenous RNA substrate.''; PubMedEurope PMCScholia
Le Hir H, Gatfield D, Izaurralde E, Moore MJ.; ''The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, Dai Q, Chen W, He C.; ''A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation.''; PubMedEurope PMCScholia
Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM.; ''Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase.''; PubMedEurope PMCScholia
Lindtner S, Felber BK, Kjems J.; ''An element in the 3' untranslated region of human LINE-1 retrotransposon mRNA binds NXF1(TAP) and can function as a nuclear export element.''; PubMedEurope PMCScholia
Katahira J, Straesser K, Saiwaki T, Yoneda Y, Hurt E.; ''Complex formation between Tap and p15 affects binding to FG-repeat nucleoporins and nucleocytoplasmic shuttling.''; PubMedEurope PMCScholia
Chi B, Wang Q, Wu G, Tan M, Wang L, Shi M, Chang X, Cheng H.; ''Aly and THO are required for assembly of the human TREX complex and association of TREX components with the spliced mRNA.''; PubMedEurope PMCScholia
Ilagan JO, Chalkley RJ, Burlingame AL, Jurica MS.; ''Rearrangements within human spliceosomes captured after exon ligation.''; PubMedEurope PMCScholia
Makarov EM, Owen N, Bottrill A, Makarova OV.; ''Functional mammalian spliceosomal complex E contains SMN complex proteins in addition to U1 and U2 snRNPs.''; PubMedEurope PMCScholia
Suntharalingam M, Wente SR.; ''Peering through the pore: nuclear pore complex structure, assembly, and function.''; PubMedEurope PMCScholia
Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, Zhao YL, Wang X, Rendtlew Danielsen JM, Liu F, Yang YG.; ''Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase.''; PubMedEurope PMCScholia
Zhou Z, Luo MJ, Straesser K, Katahira J, Hurt E, Reed R.; ''The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans.''; PubMedEurope PMCScholia
Cheng H, Dufu K, Lee CS, Hsu JL, Dias A, Reed R.; ''Human mRNA export machinery recruited to the 5' end of mRNA.''; PubMedEurope PMCScholia
Yamazaki T, Fujiwara N, Yukinaga H, Ebisuya M, Shiki T, Kurihara T, Kioka N, Kambe T, Nagao M, Nishida E, Masuda S.; ''The closely related RNA helicases, UAP56 and URH49, preferentially form distinct mRNA export machineries and coordinately regulate mitotic progression.''; PubMedEurope PMCScholia
Makarov EM, Makarova OV, Urlaub H, Gentzel M, Will CL, Wilm M, Lührmann R.; ''Small nuclear ribonucleoprotein remodeling during catalytic activation of the spliceosome.''; PubMedEurope PMCScholia
Will CL, Urlaub H, Achsel T, Gentzel M, Wilm M, Lührmann R.; ''Characterization of novel SF3b and 17S U2 snRNP proteins, including a human Prp5p homologue and an SF3b DEAD-box protein.''; PubMedEurope PMCScholia
Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, Mertins P, Ter-Ovanesyan D, Habib N, Cacchiarelli D, Sanjana NE, Freinkman E, Pacold ME, Satija R, Mikkelsen TS, Hacohen N, Zhang F, Carr SA, Lander ES, Regev A.; ''Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5' sites.''; PubMedEurope PMCScholia
Wu Q, Krainer AR.; ''AT-AC pre-mRNA splicing mechanisms and conservation of minor introns in voltage-gated ion channel genes.''; PubMedEurope PMCScholia
Kabachinski G, Schwartz TU.; ''The nuclear pore complex--structure and function at a glance.''; PubMedEurope PMCScholia
Lévesque L, Bor YC, Matzat LH, Jin L, Berberoglu S, Rekosh D, Hammarskjöld ML, Paschal BM.; ''Mutations in tap uncouple RNA export activity from translocation through the nuclear pore complex.''; PubMedEurope PMCScholia
Ruskin B, Krainer AR, Maniatis T, Green MR.; ''Excision of an intact intron as a novel lariat structure during pre-mRNA splicing in vitro.''; PubMedEurope PMCScholia
Bessonov S, Anokhina M, Krasauskas A, Golas MM, Sander B, Will CL, Urlaub H, Stark H, Lührmann R.; ''Characterization of purified human Bact spliceosomal complexes reveals compositional and morphological changes during spliceosome activation and first step catalysis.''; PubMedEurope PMCScholia
Lamond AI, Konarska MM, Grabowski PJ, Sharp PA.; ''Spliceosome assembly involves the binding and release of U4 small nuclear ribonucleoprotein.''; PubMedEurope PMCScholia
Teng IF, Wilson SA.; ''Mapping interactions between mRNA export factors in living cells.''; PubMedEurope PMCScholia
Ori A, Banterle N, Iskar M, Iskar M, Andrés-Pons A, Escher C, Khanh Bui H, Sparks L, Solis-Mezarino V, Rinner O, Bork P, Lemke EA, Beck M.; ''Cell type-specific nuclear pores: a case in point for context-dependent stoichiometry of molecular machines.''; PubMedEurope PMCScholia
Culjkovic-Kraljacic B, Borden KL.; ''Aiding and abetting cancer: mRNA export and the nuclear pore.''; PubMedEurope PMCScholia
Shepard J, Reick M, Olson S, Graveley BR.; ''Characterization of U2AF(6), a splicing factor related to U2AF(35).''; PubMedEurope PMCScholia
Charlesworth A, Meijer HA, de Moor CH.; ''Specificity factors in cytoplasmic polyadenylation.''; PubMedEurope PMCScholia
Rappsilber J, Ryder U, Lamond AI, Mann M.; ''Large-scale proteomic analysis of the human spliceosome.''; PubMedEurope PMCScholia
Ajuh P, Kuster B, Panov K, Zomerdijk JC, Mann M, Lamond AI.; ''Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry.''; PubMedEurope PMCScholia
Brahms H, Meheus L, de Brabandere V, Fischer U, Lührmann R.; ''Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B' and the Sm-like protein LSm4, and their interaction with the SMN protein.''; PubMedEurope PMCScholia
Wiegand HL, Coburn GA, Zeng Y, Kang Y, Bogerd HP, Cullen BR.; ''Formation of Tap/NXT1 heterodimers activates Tap-dependent nuclear mRNA export by enhancing recruitment to nuclear pore complexes.''; PubMedEurope PMCScholia
Wagner S, Chiosea S, Ivshina M, Nickerson JA.; ''In vitro FRAP reveals the ATP-dependent nuclear mobilization of the exon junction complex protein SRm160.''; PubMedEurope PMCScholia
Rabut G, Doye V, Ellenberg J.; ''Mapping the dynamic organization of the nuclear pore complex inside single living cells.''; PubMedEurope PMCScholia
Erkmann JA, Kutay U.; ''Nuclear export of mRNA: from the site of transcription to the cytoplasm.''; PubMedEurope PMCScholia
Kang Y, Bogerd HP, Yang J, Cullen BR.; ''Analysis of the RNA binding specificity of the human tap protein, a constitutive transport element-specific nuclear RNA export factor.''; PubMedEurope PMCScholia
Watkins JL, Murphy R, Emtage JL, Wente SR.; ''The human homologue of Saccharomyces cerevisiae Gle1p is required for poly(A)+ RNA export.''; PubMedEurope PMCScholia
Schönemann L, Kühn U, Martin G, Schäfer P, Gruber AR, Keller W, Zavolan M, Wahle E.; ''Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33.''; PubMedEurope PMCScholia
Meinel DM, Burkert-Kautzsch C, Kieser A, O'Duibhir E, Siebert M, Mayer A, Cramer P, Söding J, Holstege FC, Sträßer K.; ''Recruitment of TREX to the transcription machinery by its direct binding to the phospho-CTD of RNA polymerase II.''; PubMedEurope PMCScholia
Lin-Moshier Y, Sebastian PJ, Higgins L, Sampson ND, Hewitt JE, Marchant JS.; ''Re-evaluation of the role of calcium homeostasis endoplasmic reticulum protein (CHERP) in cellular calcium signaling.''; PubMedEurope PMCScholia
Viphakone N, Cumberbatch MG, Livingstone MJ, Heath PR, Dickman MJ, Catto JW, Wilson SA.; ''Luzp4 defines a new mRNA export pathway in cancer cells.''; PubMedEurope PMCScholia
Valadkhan S, Mohammadi A, Wachtel C, Manley JL.; ''Protein-free spliceosomal snRNAs catalyze a reaction that resembles the first step of splicing.''; PubMedEurope PMCScholia
Neubauer G, King A, Rappsilber J, Calvio C, Watson M, Ajuh P, Sleeman J, Lamond A, Mann M.; ''Mass spectrometry and EST-database searching allows characterization of the multi-protein spliceosome complex.''; PubMedEurope PMCScholia
Kang Y, Cullen BR.; ''The human Tap protein is a nuclear mRNA export factor that contains novel RNA-binding and nucleocytoplasmic transport sequences.''; PubMedEurope PMCScholia
Madan V, Kanojia D, Li J, Okamoto R, Sato-Otsubo A, Kohlmann A, Sanada M, Grossmann V, Sundaresan J, Shiraishi Y, Miyano S, Thol F, Ganser A, Yang H, Haferlach T, Ogawa S, Koeffler HP.; ''Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome.''; PubMedEurope PMCScholia
Folco EG, Lee CS, Dufu K, Yamazaki T, Reed R.; ''The proteins PDIP3 and ZC11A associate with the human TREX complex in an ATP-dependent manner and function in mRNA export.''; PubMedEurope PMCScholia
Hautbergue GM, Hung ML, Golovanov AP, Lian LY, Wilson SA.; ''Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP.''; PubMedEurope PMCScholia
Hastings ML, Krainer AR.; ''Functions of SR proteins in the U12-dependent AT-AC pre-mRNA splicing pathway.''; PubMedEurope PMCScholia
Golovanov AP, Hautbergue GM, Tintaru AM, Lian LY, Wilson SA.; ''The solution structure of REF2-I reveals interdomain interactions and regions involved in binding mRNA export factors and RNA.''; PubMedEurope PMCScholia
Deckert J, Hartmuth K, Boehringer D, Behzadnia N, Will CL, Kastner B, Stark H, Urlaub H, Lührmann R.; ''Protein composition and electron microscopy structure of affinity-purified human spliceosomal B complexes isolated under physiological conditions.''; PubMedEurope PMCScholia
Yoshimoto R, Kataoka N, Okawa K, Ohno M.; ''Isolation and characterization of post-splicing lariat-intron complexes.''; PubMedEurope PMCScholia
Box JA, Bunch JT, Tang W, Baumann P.; ''Spliceosomal cleavage generates the 3' end of telomerase RNA.''; PubMedEurope PMCScholia
Johnson SA, Kim H, Erickson B, Bentley DL.; ''The export factor Yra1 modulates mRNA 3' end processing.''; PubMedEurope PMCScholia
Bachi A, Braun IC, Rodrigues JP, Panté N, Ribbeck K, von Kobbe C, Kutay U, Wilm M, Görlich D, Carmo-Fonseca M, Izaurralde E.; ''The C-terminal domain of TAP interacts with the nuclear pore complex and promotes export of specific CTE-bearing RNA substrates.''; PubMedEurope PMCScholia
Strässer K, Masuda S, Mason P, Pfannstiel J, Oppizzi M, Rodriguez-Navarro S, Rondón AG, Aguilera A, Struhl K, Reed R, Hurt E.; ''TREX is a conserved complex coupling transcription with messenger RNA export.''; PubMedEurope PMCScholia
Chang CT, Hautbergue GM, Walsh MJ, Viphakone N, van Dijk TB, Philipsen S, Wilson SA.; ''Chtop is a component of the dynamic TREX mRNA export complex.''; PubMedEurope PMCScholia
Fontoura BM, Blobel G, Matunis MJ.; ''A conserved biogenesis pathway for nucleoporins: proteolytic processing of a 186-kilodalton precursor generates Nup98 and the novel nucleoporin, Nup96.''; PubMedEurope PMCScholia
Jurica MS, Licklider LJ, Gygi SR, Grigorieff N, Moore MJ.; ''Purification and characterization of native spliceosomes suitable for three-dimensional structural analysis.''; PubMedEurope PMCScholia
Crisci A, Raleff F, Bagdiul I, Raabe M, Urlaub H, Rain JC, Krämer A.; ''Mammalian splicing factor SF1 interacts with SURP domains of U2 snRNP-associated proteins.''; PubMedEurope PMCScholia
Shi Y, Di Giammartino DC, Taylor D, Sarkeshik A, Rice WJ, Yates JR, Frank J, Manley JL.; ''Molecular architecture of the human pre-mRNA 3' processing complex.''; PubMedEurope PMCScholia
Takagaki Y, Manley JL.; ''Complex protein interactions within the human polyadenylation machinery identify a novel component.''; PubMedEurope PMCScholia
Rougemaille M, Dieppois G, Kisseleva-Romanova E, Gudipati RK, Lemoine S, Blugeon C, Boulay J, Jensen TH, Stutz F, Devaux F, Libri D.; ''THO/Sub2p functions to coordinate 3'-end processing with gene-nuclear pore association.''; PubMedEurope PMCScholia
Luna R, Rondón AG, Aguilera A.; ''New clues to understand the role of THO and other functionally related factors in mRNP biogenesis.''; PubMedEurope PMCScholia
Zaric B, Chami M, Rémigy H, Engel A, Ballmer-Hofer K, Winkler FK, Kambach C.; ''Reconstitution of two recombinant LSm protein complexes reveals aspects of their architecture, assembly, and function.''; PubMedEurope PMCScholia
Zhao J, Hyman L, Moore C.; ''Formation of mRNA 3' ends in eukaryotes: mechanism, regulation, and interrelationships with other steps in mRNA synthesis.''; PubMedEurope PMCScholia
Lejeune F, Ishigaki Y, Li X, Maquat LE.; ''The exon junction complex is detected on CBP80-bound but not eIF4E-bound mRNA in mammalian cells: dynamics of mRNP remodeling.''; PubMedEurope PMCScholia
Degot S, Le Hir H, Alpy F, Kedinger V, Stoll I, Wendling C, Seraphin B, Rio MC, Tomasetto C.; ''Association of the breast cancer protein MLN51 with the exon junction complex via its speckle localizer and RNA binding module.''; PubMedEurope PMCScholia
Daguenet E, Baguet A, Degot S, Schmidt U, Alpy F, Wendling C, Spiegelhalter C, Kessler P, Rio MC, Le Hir H, Bertrand E, Tomasetto C.; ''Perispeckles are major assembly sites for the exon junction core complex.''; PubMedEurope PMCScholia
Braun IC, Herold A, Rode M, Conti E, Izaurralde E.; ''Overexpression of TAP/p15 heterodimers bypasses nuclear retention and stimulates nuclear mRNA export.''; PubMedEurope PMCScholia
Masuda S, Das R, Cheng H, Hurt E, Dorman N, Reed R.; ''Recruitment of the human TREX complex to mRNA during splicing.''; PubMedEurope PMCScholia
Harris ME, Böhni R, Schneiderman MH, Ramamurthy L, Schümperli D, Marzluff WF.; ''Regulation of histone mRNA in the unperturbed cell cycle: evidence suggesting control at two posttranscriptional steps.''; PubMedEurope PMCScholia
Hautbergue GM, Hung ML, Walsh MJ, Snijders AP, Chang CT, Jones R, Ponting CP, Dickman MJ, Wilson SA.; ''UIF, a New mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA.''; PubMedEurope PMCScholia
Guzik BW, Levesque L, Prasad S, Bor YC, Black BE, Paschal BM, Rekosh D, Hammarskjöld ML.; ''NXT1 (p15) is a crucial cellular cofactor in TAP-dependent export of intron-containing RNA in mammalian cells.''; PubMedEurope PMCScholia
von Moeller H, Lerner R, Ricciardi A, Basquin C, Marzluff WF, Conti E.; ''Structural and biochemical studies of SLIP1-SLBP identify DBP5 and eIF3g as SLIP1-binding proteins.''; PubMedEurope PMCScholia
Dreyfuss G, Matunis MJ, Piñol-Roma S, Burd CG.; ''hnRNP proteins and the biogenesis of mRNA.''; PubMedEurope PMCScholia
Rondón AG, Jimeno S, García-Rubio M, Aguilera A.; ''Molecular evidence that the eukaryotic THO/TREX complex is required for efficient transcription elongation.''; PubMedEurope PMCScholia
Gencheva M, Kato M, Newo AN, Lin RJ.; ''Contribution of DEAH-box protein DHX16 in human pre-mRNA splicing.''; PubMedEurope PMCScholia
Dufu K, Livingstone MJ, Seebacher J, Gygi SP, Wilson SA, Reed R.; ''ATP is required for interactions between UAP56 and two conserved mRNA export proteins, Aly and CIP29, to assemble the TREX complex.''; PubMedEurope PMCScholia
Lin DH, Stuwe T, Schilbach S, Rundlet EJ, Perriches T, Mobbs G, Fan Y, Thierbach K, Huber FM, Collins LN, Davenport AM, Jeon YE, Hoelz A.; ''Architecture of the symmetric core of the nuclear pore.''; PubMedEurope PMCScholia
Hartmuth K, Urlaub H, Vornlocher HP, Will CL, Gentzel M, Wilm M, Lührmann R.; ''Protein composition of human prespliceosomes isolated by a tobramycin affinity-selection method.''; PubMedEurope PMCScholia
Grzybowska EA.; ''Human intronless genes: functional groups, associated diseases, evolution, and mRNA processing in absence of splicing.''; PubMedEurope PMCScholia
Yao C, Choi EA, Weng L, Xie X, Wan J, Xing Y, Moresco JJ, Tu PG, Yates JR, Shi Y.; ''Overlapping and distinct functions of CstF64 and CstF64τ in mammalian mRNA 3' processing.''; PubMedEurope PMCScholia
Reichert VL, Le Hir H, Jurica MS, Moore MJ.; ''5' exon interactions within the human spliceosome establish a framework for exon junction complex structure and assembly.''; PubMedEurope PMCScholia
Katahira J, Strässer K, Podtelejnikov A, Mann M, Jung JU, Hurt E.; ''The Mex67p-mediated nuclear mRNA export pathway is conserved from yeast to human.''; PubMedEurope PMCScholia
Kaufmann I, Martin G, Friedlein A, Langen H, Keller W.; ''Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase.''; PubMedEurope PMCScholia
Viphakone N, Hautbergue GM, Walsh M, Chang CT, Holland A, Folco EG, Reed R, Wilson SA.; ''TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export.''; PubMedEurope PMCScholia
Will CL, Schneider C, Hossbach M, Urlaub H, Rauhut R, Elbashir S, Tuschl T, Lührmann R.; ''The human 18S U11/U12 snRNP contains a set of novel proteins not found in the U2-dependent spliceosome.''; PubMedEurope PMCScholia
Kosinski J, Mosalaganti S, von Appen A, Teimer R, DiGuilio AL, Wan W, Bui KH, Hagen WJ, Briggs JA, Glavy JS, Hurt E, Beck M.; ''Molecular architecture of the inner ring scaffold of the human nuclear pore complex.''; PubMedEurope PMCScholia
Behzadnia N, Golas MM, Hartmuth K, Sander B, Kastner B, Deckert J, Dube P, Will CL, Urlaub H, Stark H, Lührmann R.; ''Composition and three-dimensional EM structure of double affinity-purified, human prespliceosomal A complexes.''; PubMedEurope PMCScholia
Herold A, Suyama M, Rodrigues JP, Braun IC, Kutay U, Carmo-Fonseca M, Bork P, Izaurralde E.; ''TAP (NXF1) belongs to a multigene family of putative RNA export factors with a conserved modular architecture.''; PubMedEurope PMCScholia
Taniguchi I, Ohno M.; ''ATP-dependent recruitment of export factor Aly/REF onto intronless mRNAs by RNA helicase UAP56.''; PubMedEurope PMCScholia
Kota KP, Wagner SR, Huerta E, Underwood JM, Nickerson JA.; ''Binding of ATP to UAP56 is necessary for mRNA export.''; PubMedEurope PMCScholia
Padgett RA, Konarska MM, Grabowski PJ, Hardy SF, Sharp PA.; ''Lariat RNA's as intermediates and products in the splicing of messenger RNA precursors.''; PubMedEurope PMCScholia
Shen H, Zheng X, Luecke S, Green MR.; ''The U2AF35-related protein Urp contacts the 3' splice site to promote U12-type intron splicing and the second step of U2-type intron splicing.''; PubMedEurope PMCScholia
Wahle E, Rüegsegger U.; ''3'-End processing of pre-mRNA in eukaryotes.''; PubMedEurope PMCScholia
Grüter P, Tabernero C, von Kobbe C, Schmitt C, Saavedra C, Bachi A, Wilm M, Felber BK, Izaurralde E.; ''TAP, the human homolog of Mex67p, mediates CTE-dependent RNA export from the nucleus.''; PubMedEurope PMCScholia
Bessonov S, Anokhina M, Will CL, Urlaub H, Lührmann R.; ''Isolation of an active step I spliceosome and composition of its RNP core.''; PubMedEurope PMCScholia
Singh J, Sikand K, Conrad H, Will CL, Komar AA, Shukla GC.; ''U6atac snRNA stem-loop interacts with U12 p65 RNA binding protein and is functionally interchangeable with the U12 apical stem-loop III.''; PubMedEurope PMCScholia
The U1 snRNP is a particle consisting of the U1 snRNA and Sm core plus unique snRNP polypeptides. The U1-specific polypeptides are 70K, A, and C. The Sm core polypeptides are B, B', D1, D2, D3, E, F, G. The Sm core is a heteroheptamer in the shape of a donut, containing either B or B', which are almost identical to each other.
Histone mRNAs are exported by a mechanism that requires TAP, the key factor requires for transport of polyadenylated mRNAs. How TAP is recruited to the histone mRNAs is not known, but it is clear that transport can occur in the absence of either the stemloop or of SLBP. The mature transcript docks at the NPC, in the course of transport CBC will be lost from the mRNA cap, and remain in the nucleous.
At the beginning of this reaction, 1 molecule of 'Magoh-Y14 complex', and 1 molecule of 'Spliceosomal active C complex with lariat containing, 5'-end cleaved pre-mRNP:CBC complex' are present. At the end of this reaction, 1 molecule of 'Exon Junction Complex' is present.
The cytoplasmic 3' polyadenylated, capped intronless mRNA and TAP are released from the NPC into the cytosol. Cytosolic TAP will be recycled to the nucleous, while the 3' polyadenylated, capped intronless mRNA is bound by eIF4E and destined for translation (Carmody and Wente 2009, Wente and Rout 2010, Hetten and Kehlenbach 2007).
The mature SLBP independent intronless histone mRNA is transported through the nucler pore to the cytoplasmic side (von Moeller et al.2013). This is a black box event since there is not physical evidence about how exactly occurs this transport.
At some point eIF4E binds the mature mRNA. While TAP and Aly/Ref are released and will be reycled back to the nucleoplasm (Hung et al.2010, Lindtner et al. 2002).
Once the transport complex is fully assembled the mature mRNA can be translocated from the nucleoplasm to the cytoplasm. The assembled complex starts at the nucleoplasmic basket, travels through the pore, and ends it journey at the cytoplasmic face of the nuclear pore complex.
At some point eIF4E binds the mature mRNA. While TAP and Aly/Ref are released and will be reycled back to the nucleoplasm (Hung et al.2010, Lindtner et al. 2002).
The mRNA is transferred from ALYREF of the TREX complex to NXF1 (TAP) of the NXF1:NXT1 export complex (Hautbergue et al. 2008). Interaction between the TREX complex and NXF1 exposes the arginine-rich RNA-binding domain of NXF1 (Viphakone et al. 2012). Methylation of arginine residues on ALYREF also appears to be necessary for dissociation of mRNA from ALYREF during the transfer (Hung et al. 2010). The interaction between ALYREF and NXF1 occurs in the vicinity of nuclear speckles (Teng and Wilson 2013). DDX39B (UAP56) binds (Kota et al. 2008) and hydrolyzes ATP (Taniguchi and Ohno 2008). UAP56 is believed to hydrolyze ATP and UAP56:ADP is believed to dissociate at some point during the transfer of the mRNA to NXF1 (Taniguchi and Ohno 2008, Chang et al. 2013).
In addition to the methylation of the 5'-cap, there is methylation of internal nucleotides in the mRNA. This methylation can occur in translated and untranslated regions. One to three methyl groups have been seen per mRNA molecule, but methylation is non-stoichiometric. The most frequent methylation observed is at the N6 position of adenosine. The function of mRNA internal methylation, if any, is unknown.
After the nascent pre-mRNA undergoes the initial capping and methylation reactions, it gets associated with numerous factors, including the various heterogeneous nuclear ribonucleoproteins (hnRNPS), the nuclear Cap-Binding Complex, and many splicing factors that make the pre-mRNA a substrate for splicing, 3'-end processing, and in some cases editing.
Pre-mRNA transcripts become rapidly associated with many RNA-binding proteins, including hnRNP proteins, cap-binding proteins, SR proteins, etc; in the test tube this binding does not require splice sites or ATP. The E complex, or early complex, is the first detectable functional intermediate in spliceosome assembly in vitro. It is an ATP-independent complex. When a functional 5' splice site is present, it is bound by the U1 snRNP. The splicing factor U2AF (65 and 35 kDa subunits) binds to the polypyrimidine tract (Y)n and the AG dinucleotide at the 3' splice site, respectively. SF1/mBBP binds to the branch site. Binding of many of these factors is cooperative; e.g., SR proteins and U2AF apparently interact with each other, facilitating their binding to the pre-mRNA. In the presence of ATP, the E complex is converted to the first ATP-dependent spliceosomal complex, namely the A complex.
The A complex is the first ATP-dependent complex in spliceosome assembly. U2AF recruits the U2 snRNP to bind to the branch site in the E complex in an ATP-dependent fashion, to form the A complex. The U2 snRNA base-pairs with the branch site, causing the branch-site adenosine to bulge out, which later positions it for nucleophilic attack at the 5' splice site. The A complex serves as a substrate for formation of the B complex.
The formation of the B complex is ATP-dependent, and both the 5' and 3' splice sites are essential for B complex assembly. The U4 and U6 snRNPS are extensively base-paired, and this U4:U6 complex associates with the U5 snRNP to form a tri-snRNP particle. This tri-snRNP particle then binds to the spliceosomal A complex, to form the spliceosomal B complex.
The intermediate spliceosomal C complex (also called the Bact or B(act) complex) is a very short-lived intermediate; the splicing intermediates are rapidly converted to splicing products. Also, the spliced products are released very rapidly, and no complex containing both the splicing products has been isolated. Conversion of the spliceosomal B complex to the spliceosomal C complex requires ATP. The extensive base-pairing between the U4 and U6 snRNAs is disrupted during the formation of the C complex, which is thought to require helicase-type activity associated with the DEAD box factors. The U4 snRNP and U1 snRNP dissociate from the complex and the LSM2-6 complex of the U6 snRNP is lost, apparently allowing the U6 snRNA to then base-pair with the U2 snRNA and the 5' end of the splice site on the mRNA (Bessonov et al. 2010).
The active C complex is formed due to a conformational change in the intermediate C complex. After formation of the active C complex, the splicing reactions occur very rapidly.
In the first catalytic step of mRNA splicing, the 2' OH group of the bulged A at the branch site performs a nucleophilic attack on the 5' splice site phosphodiester bond, resulting in cleavage of the bond between the 5' exon and the 5' end of the intron, and formation of a new bond between the 5' end of the intron and the branch site A. This results in a lariat-shaped intermediate, with the intron still attached to the 3' exon. The branch site A has a 2'-5' phosphodiester bond with the G at the beginning of the intron, in addition to the usual 5'-3' and 3'-5'phosphodiester bonds.
The second step of the splicing reaction results in cleavage of the transcript at the 3'splice site, and results in ligation of the two exons and excision of the intron.
Endonucleolytic cleavage separates the pre-mRNA into an upstream fragment destined to become the mature mRNA, and a downstream fragment that is rapidly degraded. Cleavage depends on two signals in the RNA, a highly conserved hexanucleotide, AAUAAA, 10 to 30 nucleotides upstream of the cleavage site, and a poorly conserved GU- or U-rich downstream element. Additional sequences, often upstream of AAUAAA, can enhance the efficiency of the reaction. Cleavage occurs most often after a CA dinucleotide. A single gene can have more than one 3' processing site.
Cleavage is preceded by the assembly of a large processing complex, the composition of which is poorly defined. ATP, but not its hydrolysis, is required for assembly. Cleavage at the 3'-end of mRNAs depends on a number of protein factors. CPSF, a heterotetramer, binds specifically to the AAUAAA sequence. The heterotrimer CstF binds the downstream element. CF I, which appears to be composed of two subunits, one of several related larger polypeptides and a common smaller one, also binds RNA, but with unknown specificity. RNA recognition by these proteins is cooperative. Cleavage also requires CF II, composed of at least two subunits, and poly(A) polymerase, the enzyme synthesizing the poly(A) tail in the second step of the reaction. The polypeptide catalyzing the hydrolysis of the phosphodiester bond remains to be identified.
Cleavage produces a 3'-OH on the upstream fragment and a 5'-phosphate on the downstream fragment. At some unknown point after cleavage, the downstream RNA fragment, CstF, CF I and CF II are thought to be released, whereas CPSF and poly(A) polymerase remain to carry out polyadenylation.
The upstream fragment generated by 3' cleavage of the pre-mRNA receives a poly(A) tail of approximately 250 AMP residues in a reaction depending on the AAUAAA sequence 10 to 30 nucleotides upstream of the 3' end. Polyadenylation is carried out by three proteins: Poly(A) polymerase carries the catalytic activity. The enzyme has no specificity for any particular RNA sequence, and it also has a very low affinity for the RNA.
Under physiological conditions, the activity of poly(A) polymerase thus depends on two auxiliary factors, both of which bind to specific RNA sequences and recruit the enzyme by a direct contact. One of these proteins is the heterotetrameric CPSF, which binds the AAUAAA sequence and is also essential for 3' cleavage. The second is the nuclear poly(A) binding protein (PABPN1), which binds the growing poly(A) tails once this has reached a length of about ten nucleotides. Stimulation of poly(A) polymerase by both proteins is synergistic and results in processive elongation of the RNA, i.e. the polymerase adds AMP residues without dissociating from the RNA. The processive reaction is terminated when the tail has reached a length of about 250 nucleotides.
The cleavage and polyadenylation complex includes proteins that recognize the polyA addition signal of the nascent mRNA as well as the endonulcease that cleaves the RNA and other RNA binding elements (Charlesworth et al. 2013).
At the beginning of this reaction, 1 molecule of 'ATAC B Complex' is present. At the end of this reaction, 1 molecule of 'U4 ATAC snRNP', and 1 molecule of 'ATAC C Complex' are present.
This reaction takes place in the 'nucleus' (Pikielny et al.1989, Kreivi et al. 1996).
U12-type AT-AC introns are distinguished from the major U2-type introns by the consensus sequences of their highly conserved splicing signals. U12 introns have the 5' ss consensus sequence (G/A)TATCCTTT, the branchpoint sequence TTTCCTTAACT and the 3' ss (C/T)AG. Initial recognition of AT-AC introns involves interaction of U12 snRNP with the branch-point sequence and U11 with the 5' ss. Unlike the major splicing pathway, U11 and U12 are in a complex and interact with the pre-mRNA simultaneously, binding in an ATP-dependent manner as a di-snRNP complex and likely bridging the 5' ss and 3' ss region.
Twenty proteins have been identified in the U11/U12 di-snRNP complex including the snRNP Sm proteins B’, B, D3, D2, D1, E, F, and G which are identical to the major splicing pathway Sm proteins. A U2 snRNP core protein complex, SF3b is also found in the U11/U12 di-snRNP, including p14, a protein that interacts with the branchpoint adenosine.
SR proteins are required for formation of A complex in AT-AC splicing. The same SR proteins involved in splicing of the major introns are also active in splicing of AT-AC introns, though, as in the major pathway, there is substrate specificity.
The U4atac/U6atac enters the spliceosome and U6atac snRNA forms base pairing interactions with the 5' ss and also forms base pairing interactions with U12 and U4atac is partially displaced. U5 snRNP, the only snRNP common to both the major and minor splicing pathways, also joins the spliceosome to form the B complex and interacts with nucleotides within the 3' end of the exon flanking the 5' ss (Singh et al.2016, Wu and Krainer 1999).
At the beginning of this reaction, 1 molecule of 'ATAC C Complex' is present. At the end of this reaction, 1 molecule of 'ATAC C Complex with lariat containing 5'-end cleaved mRNA' is present.
This reaction takes place in the 'nucleus' (Valadkhan and Manley 2001, Valadkhan et al. 2007).
At the beginning of this reaction, 1 molecule of 'ATAC C Complex with lariat containing 5'-end cleaved mRNA' is present. At the end of this reaction, 1 molecule of 'U6 ATAC snRNP', 1 molecule of 'post exon ligation complex', 1 molecule of 'U12 snRNP', 1 molecule of 'U11 snRNP', and 1 molecule of 'U5 snRNP' are present.
At the beginning of this reaction, 1 molecule of 'TAP:3'-polyadenylated, capped mRNA complex' is present. At the end of this reaction, 1 molecule of 'SRp55', 1 molecule of 'U2AF 65 kDa subunit', 1 molecule of 'SR9 / SRp30', 1 molecule of 'hTra2', 1 molecule of 'hPrp16', 1 molecule of 'SR 11/ p54', 1 molecule of 'hPrp22', 1 molecule of 'SRp40', 1 molecule of 'hPrp17', 1 molecule of 'SF2/ASF/SFRS1', 1 molecule of 'hSLU7', 1 molecule of 'Export Receptor bound mature mRNA Complex', 1 molecule of 'U2AF 35 kDa subunit', 1 molecule of 'SR2 / SC35', 1 molecule of 'hPrp43', 1 molecule of 'SRp20', 1 molecule of 'SR7/ 9G8 protein', 1 molecule of 'hPrp18', and 1 molecule of 'SR4 / SRp75' are present.
At the beginning of this reaction, 1 molecule of and 1 molecule of 'Export Receptor bound mature mRNA Complex' are present. At the end of this reaction, 1 molecule of 'THOC4(Aly/Ref)', 1 molecule of 'Mature mRNP Complex', 1 molecule of 'SRm160', and 1 molecule of 'TAP' are present.
Histone mRNAs are exported by a mechanism that requires TAP, the key factor requires for transport of polyadenylated mRNAs. How TAP is recruited to the histone mRNAs is not known, but it is clear that transport can occur in the absence of either the stemloop or of SLBP. The stemloop and SLBP enhance the rate of transport of histone mRNAs in Xenopus oocytes, but are not essential for transport
The polyadenylated, capped transcript and TAP dock at the nucleoplasmic side of the NPC. The Cap Binding Complex (CBC) and CPSF complexes are released back into the nucleoplasm (Zhou et al. 2000).
The THO subcomplex of the TREX complex initially interacts with the serine-2,5 phosphorylated C-terminal domain of RNA polymerase II (Strasser et al. 2002, Inferred from yeast in Meinel et al. 2013) then with CBP80 of the cap binding complex (Cheng et al. 2006, Dufu et al. 2010, Chi et al. 2013). A TREX complex binds spliced mRNA near the cap during transcription (Cheng et al. 2006). Recruitment is dependent on splicing of the mRNA (Masuda et al. 2005). THO/TREX is required for efficient mRNP biogenesis and export (reviewed in Luna et al 2012). In yeast, components of the THO/TREX complex also affect transcription and 3' processing of mRNA, (Rondon et al. 2003, Rougemaille et al. 2008, Johnson et al. 2011, reviewed in Katahira 2015), however the human TREX complex does not appear to affect transcription (Masuda et al. 2005). The AREX complex, which contains DDX39A (UHR49) rather than DDX39B (UAP56) appears to perform the same function as TREX in mRNA export, but acts on a different subset of mRNAs (Yamazaki et al. 2010).
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DataNodes
ligated exon
containing complexlariat containing
5'-end cleaved mRNAPolyadenylation
ComplexIntronless transcript derived Histone
mRNA:SLBP:CBP80:CBP20intronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexintronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexTranscript Derived Histone mRNA:TAP:Aly/Ref
ComplexTranscript Derived Histone mRNA:TAP:Aly/Ref
complexTranscript Derived
mRNA:eIF4E Complexindependent Histone
mRNA:eIF4E complexderived mRNA:TAP:Aly/Ref
complexderived mRNA
complextranscript derived Histone mRNA:SLBP:eIF4E
Complextranscript derived Histone pre-mRNA:CBC
complexintronless derived mRNA:TAP:Aly/Ref
complexpolymerase II
(phosphorylated):TFIIF complexIntermediate C
(Bact) ComplexC complex with lariat containing, 5'-end cleaved pre-mRNP:CBC
complexpre-mRNA:CBC:RNA Pol II (phosphorylated)
complexpre-mRNA:CBC
Complexpre-mRNP:CBC
complexcapped
mRNA:CBC:EJC:TREX:SRSF proteinsAnnotated Interactions
ligated exon
containing complexligated exon
containing complexlariat containing
5'-end cleaved mRNAlariat containing
5'-end cleaved mRNAPolyadenylation
ComplexPolyadenylation
ComplexIntronless transcript derived Histone
mRNA:SLBP:CBP80:CBP20intronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexintronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexintronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexintronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexTranscript Derived Histone mRNA:TAP:Aly/Ref
ComplexTranscript Derived Histone mRNA:TAP:Aly/Ref
ComplexTranscript Derived Histone mRNA:TAP:Aly/Ref
complexTranscript Derived Histone mRNA:TAP:Aly/Ref
complexTranscript Derived
mRNA:eIF4E Complexindependent Histone
mRNA:eIF4E complexderived mRNA:TAP:Aly/Ref
complexderived mRNA:TAP:Aly/Ref
complexderived mRNA
complextranscript derived Histone mRNA:SLBP:eIF4E
Complextranscript derived Histone pre-mRNA:CBC
complexintronless derived mRNA:TAP:Aly/Ref
complexintronless derived mRNA:TAP:Aly/Ref
complexThis reaction takes place in the 'nucleoplasm'.
Cleavage is preceded by the assembly of a large processing complex, the composition of which is poorly defined. ATP, but not its hydrolysis, is required for assembly. Cleavage at the 3'-end of mRNAs depends on a number of protein factors. CPSF, a heterotetramer, binds specifically to the AAUAAA sequence. The heterotrimer CstF binds the downstream element. CF I, which appears to be composed of two subunits, one of several related larger polypeptides and a common smaller one, also binds RNA, but with unknown specificity. RNA recognition by these proteins is cooperative. Cleavage also requires CF II, composed of at least two subunits, and poly(A) polymerase, the enzyme synthesizing the poly(A) tail in the second step of the reaction. The polypeptide catalyzing the hydrolysis of the phosphodiester bond remains to be identified.
Cleavage produces a 3'-OH on the upstream fragment and a 5'-phosphate on the downstream fragment. At some unknown point after cleavage, the downstream RNA fragment, CstF, CF I and CF II are thought to be released, whereas CPSF and poly(A) polymerase remain to carry out polyadenylation.
Under physiological conditions, the activity of poly(A) polymerase thus depends on two auxiliary factors, both of which bind to specific RNA sequences and recruit the enzyme by a direct contact. One of these proteins is the heterotetrameric CPSF, which binds the AAUAAA sequence and is also essential for 3' cleavage. The second is the nuclear poly(A) binding protein (PABPN1), which binds the growing poly(A) tails once this has reached a length of about ten nucleotides. Stimulation of poly(A) polymerase by both proteins is synergistic and results in processive elongation of the RNA, i.e. the polymerase adds AMP residues without dissociating from the RNA. The processive reaction is terminated when the tail has reached a length of about 250 nucleotides.
This reaction takes place in the 'nucleus' (Pikielny et al.1989, Kreivi et al. 1996).
Twenty proteins have been identified in the U11/U12 di-snRNP complex including the snRNP Sm proteins B’, B, D3, D2, D1, E, F, and G which are identical to the major splicing pathway Sm proteins. A U2 snRNP core protein complex, SF3b is also found in the U11/U12 di-snRNP, including p14, a protein that interacts with the branchpoint adenosine.
SR proteins are required for formation of A complex in AT-AC splicing. The same SR proteins involved in splicing of the major introns are also active in splicing of AT-AC introns, though, as in the major pathway, there is substrate specificity.
This reaction takes place in the 'nucleus' (Valadkhan and Manley 2001, Valadkhan et al. 2007).
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleoplasm'.
This reaction takes place in the 'nuclear envelope'.
This reaction takes place in the 'cytoplasm'.
polymerase II
(phosphorylated):TFIIF complexIntermediate C
(Bact) ComplexIntermediate C
(Bact) ComplexIntermediate C
(Bact) ComplexC complex with lariat containing, 5'-end cleaved pre-mRNP:CBC
complexC complex with lariat containing, 5'-end cleaved pre-mRNP:CBC
complexpre-mRNA:CBC:RNA Pol II (phosphorylated)
complexpre-mRNA:CBC
Complexpre-mRNA:CBC
Complexpre-mRNA:CBC
Complexpre-mRNP:CBC
complexpre-mRNP:CBC
complexcapped
mRNA:CBC:EJC:TREX:SRSF proteinscapped
mRNA:CBC:EJC:TREX:SRSF proteinscapped
mRNA:CBC:EJC:TREX:SRSF proteins