Precursor messenger RNA (pre-mRNA) splicing is a critical step in the posttranscriptional regulation of gene expression, providing significant expansion of the functional proteome of eukaryotic organisms with limited gene numbers. Split eukaryotic genes contain intervening sequences or introns disrupting protein-coding exons, and intron removal occurs by repeated assembly of a large and highly dynamic ribonucleoprotein complex termed the spliceosome, which is composed of five small nuclear ribonucleoprotein particles, U1, U2, U4/U6, and U5. Biochemical studies over the past 10 years have allowed the isolation as well as compositional, functional, and structural analysis of splicing complexes at distinct stages along the spliceosome cycle. The average human gene contains eight exons and seven introns, producing an average of three or more alternatively spliced mRNA isoforms. Recent high-throughput sequencing studies indicate that 100% of human genes produce at least two alternative mRNA isoforms. Mechanisms of alternative splicing include RNA–protein interactions of splicing factors with regulatory sites termed silencers or enhancers, RNA–RNA base-pairing interactions, or chromatin-based effects that can change or determine splicing patterns. Disease-causing mutations can often occur in splice sites near intron borders or in exonic or intronic RNA regulatory silencer or enhancer elements, as well as in genes that encode splicing factors. Together, these studies provide mechanistic insights into how spliceosome assembly, dynamics, and catalysis occur; how alternative splicing is regulated and evolves; and how splicing can be disrupted by - and -acting mutations leading to disease states. These findings make the spliceosome an attractive new target for small-molecule, antisense, and genome-editing therapeutic interventions.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Sharp PA. 1.  1994. Split genes and RNA splicing. Cell 77:805–15 [Google Scholar]
  2. Sharp PA. 2.  2005. The discovery of split genes and RNA splicing. Trends Biochem. Sci. 30:279–81 [Google Scholar]
  3. Kim E, Magen A, Ast G. 3.  2007. Different levels of alternative splicing among eukaryotes. Nucleic Acids Res. 35:125–31 [Google Scholar]
  4. Kim H, Klein R, Majewski J, Ott J. 4.  2004. Estimating rates of alternative splicing in mammals and invertebrates. Nat. Genet. 36:915–17 [Google Scholar]
  5. Merkin J, Russell C, Chen P, Burge CB. 5.  2012. Evolutionary dynamics of gene and isoform regulation in mammalian tissues. Science 338:1593–99 [Google Scholar]
  6. Barbosa-Morais NL, Irimia M, Pan Q, Xiong HY, Gueroussov S. 6.  et al. 2012. The evolutionary landscape of alternative splicing in vertebrate species. Science 338:1587–93 [Google Scholar]
  7. Nilsen TW, Graveley BR. 7.  2010. Expansion of the eukaryotic proteome by alternative splicing. Nature 463:457–63 [Google Scholar]
  8. Irimia M, Blencowe BJ. 8.  2012. Alternative splicing: decoding an expansive regulatory layer. Curr. Opin. Cell Biol. 24:323–32 [Google Scholar]
  9. Braunschweig U, Gueroussov S, Plocik AM, Graveley BR, Blencowe BJ. 9.  2013. Dynamic integration of splicing within gene regulatory pathways. Cell 152:1252–69 [Google Scholar]
  10. Kelemen O, Convertini P, Zhang Z, Wen Y, Shen M. 10.  et al. 2013. Function of alternative splicing. Gene 514:1–30 [Google Scholar]
  11. Wahl MC, Will CL, Lührmann R. 11.  2009. The spliceosome: design principles of a dynamic RNP machine. Cell 136:701–18 [Google Scholar]
  12. Will CL, Lührmann R. 12.  2011. Spliceosome structure and function. Cold Spring Harb. Perspect. Biol. 3:a003707 [Google Scholar]
  13. Fica SM, Tuttle N, Novak T, Li N-S, Lu J. 13.  et al. 2013. RNA catalyses nuclear pre-mRNA splicing. Nature 503:229–34 [Google Scholar]
  14. Chen M, Manley JL. 14.  2009. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat. Rev. Mol. Cell Biol. 10:741–54 [Google Scholar]
  15. Licatalosi DD, Darnell RB. 15.  2010. RNA processing and its regulation: global insights into biological networks. Nat. Rev. Genet. 11:75–87 [Google Scholar]
  16. Olson S, Blanchette M, Park J, Savva Y, Yeo GW. 16.  et al. 2007. A regulator of Dscam mutually exclusive splicing fidelity. Nat. Struct. Mol. Biol. 14:1134–40 [Google Scholar]
  17. Kishore S, Stamm S. 17.  2006. Regulation of alternative splicing by snoRNAs. Cold Spring Harb. Symp. Quant. Biol. 71:329–34 [Google Scholar]
  18. Kishore S, Stamm S. 18.  2006. The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311:230–32 [Google Scholar]
  19. Allemand E, Batsche E, Muchardt C. 19.  2008. Splicing, transcription, and chromatin: a menage a trois. Curr. Opin. Genet. Dev. 18:145–51 [Google Scholar]
  20. Luco RF, Alló M, Schor IE, Kornblihtt AR, Misteli T. 20.  2011. Epigenetics in alternative pre-mRNA splicing. Cell 144:16–26 [Google Scholar]
  21. Zhou HL, Luo G, Wise JA, Lou H. 21.  2014. Regulation of alternative splicing by local histone modifications: potential roles for RNA-guided mechanisms. Nucleic Acids Res. 42:701–13 [Google Scholar]
  22. Meister G. 22.  2013. Argonaute proteins: functional insights and emerging roles. Nat. Rev. Genet. 14:447–59 [Google Scholar]
  23. Huang V, Li LC. 23.  2014. Demystifying the nuclear function of Argonaute proteins. RNA Biol. 11:18–24 [Google Scholar]
  24. Cecere G, Grishok A. 24.  2014. A nuclear perspective on RNAi pathways in metazoans. Biochim. Biophys. Acta 1839:223–33 [Google Scholar]
  25. Dujardin G, Lafaille C, Petrillo E, Buggiano V, Gómez Acuña LI. 25.  et al. 2013. Transcriptional elongation and alternative splicing. Biochim. Biophys. Acta 1829:134–40 [Google Scholar]
  26. Gómez Acuña LI, Fiszbein A, Alló M, Schor IE, Kornblihtt AR. 26.  2013. Connections between chromatin signatures and splicing. Wiley Interdiscip Rev. RNA 4:77–91 [Google Scholar]
  27. Dujardin G, Lafaille C, de la Mata M, Marasco LE, Muñoz MJ. 27.  et al. 2014. How slow RNA polymerase II elongation favors alternative exon skipping. Mol. Cell 54:683–90 [Google Scholar]
  28. Cooper TA, Wan L, Dreyfuss G. 28.  2009. RNA and disease. Cell 136:777–93 [Google Scholar]
  29. Padgett RA. 29.  2012. New connections between splicing and human disease. Trends Genet. 28:147–54 [Google Scholar]
  30. Krawczak M, Reiss J, Cooper DN. 30.  1992. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum. Genet. 90:41–54 [Google Scholar]
  31. Cartegni L, Chew SL, Krainer AR. 31.  2002. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat. Rev. Genet. 3:285–98 [Google Scholar]
  32. Pagani F, Baralle FE. 32.  2004. Genomic variants in exons and introns: identifying the splicing spoilers. Nat. Rev. Genet. 5:389–96 [Google Scholar]
  33. Krawczak M, Thomas NS, Hundreiser B, Mort M, Wittig M. 33.  et al. 2007. Single base-pair substitutions in exon–intron junctions of human genes: nature, distribution, and consequences for mRNA splicing. Hum. Mutat. 28:150–58 [Google Scholar]
  34. ElSharawy AGA, Hundreiser B, Brosch M, Wittig M, Huse K. 34.  et al. 2009. Systematic evaluation of the effect of common SNPs on pre-mRNA splicing. Hum. Mutat. 30:625–32 [Google Scholar]
  35. Supek F, Miñana B, Valcárcel J, Gabaldón T, Lehner B. 35.  2014. Synonymous mutations frequently act as driver mutations in human cancers. Cell 156:1324–35 [Google Scholar]
  36. Ogawa S. 36.  2012. Splicing factor mutations in myelodysplasia. Int. J. Hematol. 96:438–42 [Google Scholar]
  37. Maciejewski JP, Padgett RA. 37.  2012. Defects in spliceosomal machinery: a new pathway of leukaemogenesis. Br. J. Haematol. 158:165–73 [Google Scholar]
  38. Makishima H, Visconte V, Sakaguchi H, Jankowska AM, Abu Kar S. 38.  et al. 2012. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 119:3203–10 [Google Scholar]
  39. Auboeuf D, Carno-Fonseca M, Valcárcel J, Biamonti G. 39.  2012. Alternative splicing and cancer. J. Nucleic Acids 2012:363809 [Google Scholar]
  40. Tazi J, Durand S, Jeanteur P. 40.  2005. The spliceosome: a novel multi-faceted target for therapy. Trends Biochem. Sci. 30:469–78 [Google Scholar]
  41. Bonnal S, Vigevani L, Valcárcel J. 41.  2012. The spliceosome as a target of novel antitumour drugs. Nat. Rev. Drug Discov. 11:847–59 [Google Scholar]
  42. Cartegni L, Krainer AR. 42.  2003. Correction of disease-associated exon skipping by synthetic exon-specific activators. Nat. Struct. Biol. 10:120–25 [Google Scholar]
  43. Hua Y, Vickers TA, Okunola HL, Bennett F, Krainer AR. 43.  2008. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am. J. Hum. Genet. 82:834–48 [Google Scholar]
  44. Sahashi K, Hua Y, Ling KK, Hung G, Rigo F. 44.  et al. 2012. TSUNAMI: an antisense method to phenocopy splicing-associated diseases in animals. Genes Dev. 26:1874–84 [Google Scholar]
  45. Mali P, Esvelt KM, Church GM. 45.  2013. Cas9 as a versatile tool for engineering biology. Nat. Methods 10:957–63 [Google Scholar]
  46. Yin H, Xue W, Chen S, Bogorad RL, Benedetti E. 46.  et al. 2014. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat. Biotechnol. 32:551–53 [Google Scholar]
  47. Hartmuth K, Vornlocher HP, Lührmann R. 47.  2004. Tobramycin affinity tag purification of spliceosomes. Methods Mol. Biol. 257:47–64 [Google Scholar]
  48. Zhou Z, Licklider LJ, Gygi SP, Reed R. 48.  2002. Comprehensive proteomic analysis of the human spliceosome. Nature 419:182–85 [Google Scholar]
  49. Zhou Z, Sim J, Griffith J, Reed R. 49.  2002. Purification and electron microscopic visualization of functional human spliceosomes. PNAS 99:12203–7 [Google Scholar]
  50. Jurica MS, Moore MJ. 50.  2002. Capturing splicing complexes to study structure and mechanism. Methods 28:336–45 [Google Scholar]
  51. Herold N, Will CL, Wolf E, Kastner B, Urlaub H, Lührmann R. 51.  2009. Conservation of the protein composition and electron microscopy structure of Drosophila melanogaster and human spliceosomal complexes. Mol. Cell. Biol. 29:281–301 [Google Scholar]
  52. Fabrizio P, Dannenberg J, Dube P, Kastner P, Stark H. 52.  et al. 2009. The evolutionarily conserved core design of the catalytic activation step of the yeast spliceosome. Mol. Cell 36:593–608 [Google Scholar]
  53. Jurica MS, Moore MJ. 53.  2003. Pre-mRNA splicing: awash in a sea of proteins. Mol. Cell 12:5–14 [Google Scholar]
  54. Hegele A, Kamburov A, Grossman A, Sourlis C, Wowro S. 54.  et al. 2012. Dynamic protein–protein interaction wiring of the human spliceosome. Mol. Cell 45:567–80 [Google Scholar]
  55. Häcker I, Sander B, Golas MM, Karagöz E, Kastner B. 55.  et al. 2008. Localization of Prp8, Brr2, Snu114 and U4/U6 proteins in the yeast tri-snRNP by electron microscopy. Nat. Struct. Mol. Biol. 15:1206–12 [Google Scholar]
  56. Behzadnia N, Golas MM, Harmuth K, Sander B, Deckert J. 56.  et al. 2007. Composition and three-dimensional EM structure of double affinity-purified, human prespliceosomal A complexes. EMBO J. 26:1737–48 [Google Scholar]
  57. Deckert J, Harmuth K, Boehringer D, Behzadnia N, Will CL. 57.  et al. 2006. Protein composition and electron microscopy structure of affinity-purified human spliceosomal B complexes isolated under physiological conditions. Mol. Cell. Biol. 26:5528–43 [Google Scholar]
  58. Bessonov S, Anokhina M, Krasauskas A, Golas MM, Sander B. 58.  et al. 2010. Characterization of purified human Bact spliceosomal complexes reveals compositional and morphological changes during spliceosome activation and first step catalysis. RNA 16:2384–403 [Google Scholar]
  59. Golas MM, Sander B, Bessonov S, Grote M, Wolf E. 59.  et al. 2010. 3D cryo-EM structure of an active step I spliceosome and localization of its catalytic core. Mol. Cell 40:927–38 [Google Scholar]
  60. Jurica MS, Sousa D, Moore MJ, Girgorieff N. 60.  2004. Three-dimensional structure of C complex spliceosomes by electron microscopy. Nat. Struct. Mol. Biol. 11:265–69 [Google Scholar]
  61. Boehringer D, Makarov EM, Sander B, Markaova OV, Kastner B. 61.  et al. 2004. Three-dimensional structure of a pre-catalytic human spliceosomal complex B. Nat. Struct. Mol. Biol. 11:463–68 [Google Scholar]
  62. Warkocki Z, Odenwälder P, Schmitzová J, Platzmann F, Stark H. 62.  et al. 2009. Reconstitution of both steps of Saccharomyces cerevisiae splicing with purified spliceosomal components. Nat. Struct. Mol. Biol. 16:1237–43 [Google Scholar]
  63. Stark H, Lührmann R. 63.  2006. Cryo–electron microscopy of spliceosomal components. Annu. Rev. Biophys. Biomol. Struct. 35:435–57 [Google Scholar]
  64. Pomeranz Krummel DA, Oubridge C, Leung AKW, Li J, Nagai K. 64.  2009. Crystal structure of human spliceosomal U1 snRNP at 5.5 Å resolution. Nature 458:475–80 [Google Scholar]
  65. Oubridge C, Ito N, Evans PR, Teo C-H, Nagai K. 65.  1994. Crystal structure at 1.92 Å resolution of the RNA-binding domain of the U1A spliceosomal protein complexed with an RNA hairpin. Nature 372:432–38 [Google Scholar]
  66. Weber G, Trowitzsch S, Kastner B, Lührmann R, Wahl MC. 66.  2010. Functional organization of the Sm core in the crystal structure of human U1 snRNP. EMBO J. 29:4172–84 [Google Scholar]
  67. Montemayor EJ, Curran EC, Liao HH, Andrews KL, Treba CN. 67.  et al. 2014. Core structure of the U6 small nuclear ribonucleoprotein at 1.7-Å resolution. Nat. Struct. Mol. Biol. 21:544–51 [Google Scholar]
  68. Leung AK, Nagai K, Li J. 68.  2011. Structure of the spliceosomal U4 snRNP core domain and its implication for snRNP biogenesis. Nature 473:536–39 [Google Scholar]
  69. Bessonov S, Anokhina M, Will CL, Urlaub H, Lührmann R. 69.  2008. Isolation of an active step I spliceosome and composition of its RNP core. Nature 452:846–50 [Google Scholar]
  70. Tseng CK, Cheng SC. 70.  2008. Both catalytic steps of nuclear pre-mRNA splicing are reversible. Science 320:1782–84 [Google Scholar]
  71. Hoskins AA, Gelles J, Moore MJ. 71.  2011. New insights into the spliceosome by single molecule fluorescence microscopy. Curr. Opin. Chem. Biol. 15:864–70 [Google Scholar]
  72. Crawford DJ, Hoskins AA, Friedman LJ, Gelles J, Moore MJ. 72.  2008. Visualizing the splicing of single pre-mRNA molecules in whole cell extract. RNA 14:170–79 [Google Scholar]
  73. Hoskins AA, Friedman LJ, Gallagher SS, Crawford DJ, Anderson EG. 73.  et al. 2011. Ordered and dynamic assembly of single spliceosomes. Science 331:1289–95 [Google Scholar]
  74. Shcherbakova I, Hoskins AA, Friedman LJ, Serebrov V, Correa IR Jr. 74.  2013. Alternative spliceosome assembly pathways revealed by single-molecule fluorescence microscopy. Cell Rep. 5:151–65 [Google Scholar]
  75. Crawford DJ, Hoskins AA, Friedman LJ, Gelles J, Moore MJ. 75.  2013. Single-molecule colocalization FRET evidence that spliceosome activation precedes stable approach of 5′ splice site and branch site. PNAS 110:6783–88 [Google Scholar]
  76. Abelson J, Blanco M, Ditzler MA, Fuller F, Aravamudhan P. 76.  et al. 2010. Conformational dynamics of single pre-mRNA molecules during in vitro splicing. Nat. Struct. Mol. Biol. 17:504–12 [Google Scholar]
  77. Marcia M, Pyle AM. 77.  2012. Visualizing group II intron catalysis through the stages of splicing. Cell 151:497–507 [Google Scholar]
  78. Fica SM, Mefford MA, Piccirilli JA, Staley JP. 78.  2014. Evidence for a group II intron–like catalytic triplex in the spliceosome. Nat. Struct. Mol. Biol. 21:464–71 [Google Scholar]
  79. Smith DJ, Query CC, Konarska MM. 79.  2008. “Nought may endure but mutability”: spliceosome dynamics and the regulation of splicing. Mol. Cell 30:657–66 [Google Scholar]
  80. Newman AJ, Nagai K. 80.  2010. Structural studies of the spliceosome: blind men and an elephant. Curr. Opin. Struct. Biol. 20:82–89 [Google Scholar]
  81. Pena V, Rozov A, Fabrizio P, Lührmann R, Wahl MC. 81.  2008. Structure and function of an RNase H domain at the heart of the spliceosome. EMBO J. 27:2929–40 [Google Scholar]
  82. Schellenberg MJ, Ritchie DB, MacMillan AM. 82.  2008. Pre-mRNA splicing: a complex picture in higher definition. Trends Biochem. Sci. 33:243–46 [Google Scholar]
  83. Galej WP, Oubridge C, Newman AJ, Nagai K. 83.  2013. Crystal structure of Prp8 reveals active site cavity of the spliceosome. Nature 493:638–43 [Google Scholar]
  84. Galej WP, Nguyen THD, Newman AJ, Nagai K. 84.  2014. Structural studies of the spliceosome: zooming into the heart of the machine. Curr. Opin. Struct. Biol. 25:57–66 [Google Scholar]
  85. Schellenberg MJ, Wu T, Ritchie DB, Fica S, Staley JP. 85.  et al. 2013. A conformational switch in PRP8 mediates metal ion coordination that promotes pre-mRNA exon ligation. Nat. Struct. Mol. Biol. 20:728–34 [Google Scholar]
  86. Valadkhan S, Manley JL. 86.  2001. Splicing-related catalysis by protein-free snRNAs. Nature 413:701–7 [Google Scholar]
  87. Valadkhan S, Manley JL. 87.  2003. Characterization of the catalytic activity of U2 and U6 snRNAs. RNA 9:892–904 [Google Scholar]
  88. Sontheimer EJ, Sun S, Piccirilli JA. 88.  1997. Metal ion catalysis during splicing of premessenger RNA. Nature 388:801–5 [Google Scholar]
  89. Fabrizio P, McPheeters DS, Abelson J. 89.  1989. In vitro assembly of yeast U6 snRNP: a functional assay. Genes Dev. 3:2137–50 [Google Scholar]
  90. Treisman R, Orkin SH, Maniatis T. 90.  1983. Specific transcription and RNA splicing defects in five cloned β-thalassaemia genes. Nature 302:591–96 [Google Scholar]
  91. Treisman R, Proudfoot NJ, Shander M, Maniatis T. 91.  1982. A single-base change at a splice site in a β0-thalassemic gene causes abnormal RNA splicing. Cell 29:903–11 [Google Scholar]
  92. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. 92.  2008. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat. Genet. 40:1413–15 [Google Scholar]
  93. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L. 93.  et al. 2008. Alternative isoform regulation in human tissue transcriptomes. Nature 456:470–76 [Google Scholar]
  94. Kashima T, Manley JL. 94.  2003. A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat. Genet. 34:460–63 [Google Scholar]
  95. Cartegni L, Krainer AR. 95.  2002. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat. Genet. 30:377–84 [Google Scholar]
  96. David CJ, Chen M, Assanah M, Canoll P, Manley JL. 96.  2010. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463:364–68 [Google Scholar]
  97. Kashima T, Rao N, David CJ, Manley JL. 97.  2007. hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing. Hum. Mol. Genet. 16:3149–59 [Google Scholar]
  98. Wang Z, Chatterjee D, Jeon HY, Akerman M, Vander Heiden MG. 98.  et al. 2012. Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons. J. Mol. Cell Biol. 4:79–87 [Google Scholar]
  99. David CJ, Manley JL. 99.  2010. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev. 24:2343–64 [Google Scholar]
  100. Lovci MT, Ghanem D, Marr H, Arnold J, Gee S. 100.  et al. 2013. Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges. Nat. Struct. Mol. Biol. 20:1434–42 [Google Scholar]
  101. Zhang J, Manley JL. 101.  2013. Misregulation of pre-mRNA alternative splicing in cancer. Cancer Discov. 3:1228–37 [Google Scholar]
  102. Kim HJ, Kim NC, Wang Y-D, Scarborough EA, Moore J. 102.  et al. 2013. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–73 [Google Scholar]
  103. King OD, Gitler AD, Shorter J. 103.  2012. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. 1462:61–80 [Google Scholar]
  104. Kwon I, Kato M, Xiang S, Wu L, Theodoropoulos P. 104.  et al. 2013. Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 155:1049–60 [Google Scholar]
  105. Hahn CN, Scott HS. 105.  2012. Spliceosome mutations in hematopoietic malignancies. Nat. Genet. 44:9–10 [Google Scholar]
  106. Przychodzen B, Jerez A, Guinta K, Sekeres MA, Padgett R. 106.  et al. 2013. Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. Blood 122:999–1006 [Google Scholar]
  107. Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ. 107.  et al. 2012. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150:1107–20 [Google Scholar]
  108. Brooks AN, Choi PS, de Waal L, Sharifnia T, Imielinksi M. 108.  et al. 2014. A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events. PLOS ONE 9:e87361 [Google Scholar]
  109. Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR. 109.  2007. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat. Struct. Mol. Biol. 14:185–93 [Google Scholar]
  110. Karni R, Hippo Y, Lowe SW, Krainer AR. 110.  2008. The splicing-factor oncoprotein SF2/ASF activates mTORC1. PNAS 105:15323–27 [Google Scholar]
  111. Kaida D, Motoyoshi H, Tashiro E, Nojima T, Hagiwara M. 111.  et al. 2007. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat. Chem. Biol. 3:576–83 [Google Scholar]
  112. Roybal GA, Jurica MS. 112.  2010. Spliceostatin A inhibits spliceosome assembly subsequent to prespliceosome formation. Nucleic Acids Res. 38:6664–72 [Google Scholar]
  113. Effenberger KA, Perriman RJ, Bray WM, Lokey RS, Ares M Jr, Jurica MS. 113.  2013. A high-throughput splicing assay identifies new classes of inhibitors of human and yeast spliceosomes. J. Biomol. Screen. 18:1110–20 [Google Scholar]
  114. Ilagan JO, Jurica MS. 114.  2014. Isolation and accumulation of spliceosomal assembly intermediates. Methods Mol. Biol. 1126:179–92 [Google Scholar]
  115. Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP. 115.  et al. 2011. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci. Transl. Med. 3:72ra18 [Google Scholar]
  116. Hua Y, Sahashi K, Rigo F, Hung G, Horev G. 116.  et al. 2011. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478:123–26 [Google Scholar]
  117. Rigo F, Hua Y, Krainer AR, Bennett CF. 117.  2012. Antisense-based therapy for the treatment of spinal muscular atrophy. J. Cell Biol. 199:21–25 [Google Scholar]
  118. Black DL. 118.  2003. Mechanisms of alternative pre-messenger RNA splicing. Annu. Rev. Biochem. 72:291–336 [Google Scholar]
  119. Blencowe BJ. 119.  2006. Alternative splicing: new insights from global analyses. Cell 126:37–47 [Google Scholar]
  120. Wang Z, Burge CB. 120.  2008. Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA 14:802–13 [Google Scholar]
  121. Martinez-Contreras R, Cloutier P, Shkreta L, Fisette JF, Revil T, Chabot B. 121.  2007. hnRNP proteins and splicing control. Adv. Exp. Med. Biol. 623:123–47 [Google Scholar]
  122. Long JC, Caceres JF. 122.  2009. The SR protein family of splicing factors: master regulators of gene expression. Biochem. J. 417:15–27 [Google Scholar]
  123. Manley JL, Krainer AR. 123.  2010. A rational nomenclature for serine/arginine-rich protein splicing factors (SR proteins). Genes Dev. 24:1073–74 [Google Scholar]
  124. Änkö ML. 124.  2014. Regulation of gene expression programmes by serine–arginine rich splicing factors. Semin. Cell Dev. Biol. 32:11–21 [Google Scholar]
  125. Zhou Z, Fu XD. 125.  2013. Regulation of splicing by SR proteins and SR protein-specific kinases. Chromosoma 122:191–207 [Google Scholar]
  126. Darnell RB. 126.  2013. RNA protein interaction in neurons. Annu. Rev. Neurosci. 36:243–70 [Google Scholar]
  127. Zhang C, Zhang Z, Castle J, Sun S, Johnson J. 127.  et al. 2008. Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2. Genes Dev. 22:2550–63 [Google Scholar]
  128. Yeo GW, Coufal NG, Liang TY, Peng GE, Fu XD, Gage FH. 128.  2009. An RNA code for the FOX2 splicing regulator revealed by mapping RNA–protein interactions in stem cells. Nat. Struct. Mol. Biol. 16:130–37 [Google Scholar]
  129. Weyn-Vanhentenryck SM, Mele A, Yan Q, Sun S, Farny N. 129.  et al. 2014. HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism. Cell Rep. 6:1139–52 [Google Scholar]
  130. Wang ET, Cody NAL, Jog S, Biancolella M, Wang TT. 130.  et al. 2012. Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell 150:710–24 [Google Scholar]
  131. Han H, Irimia M, Ross PJ, Sung H-K, Alipanahi B. 131.  et al. 2013. MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature 498:241–45 [Google Scholar]
  132. Pandit S, Zhou Y, Shiue L, Coutinho-Mansfield G, Li H. 132.  et al. 2013. Genome-wide analysis reveals SR protein cooperation and competition in regulated splicing. Mol. Cell 50:223–35 [Google Scholar]
  133. Jean-Philippe J, Paz S, Caputi M. 133.  2013. hnRNP A1: the Swiss army knife of gene expression. Int. J. Mol. Sci. 14:18999–9024 [Google Scholar]
  134. Huelga SC, Vu AQ, Arnold JD, Liang TY, Liu PP. 134.  et al. 2012. Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins. Cell Rep. 1:167–78 [Google Scholar]
  135. Blanchette M, Green RE, MacArthur S, Brooks AN, Brenner SE. 135.  et al. 2009. Genome-wide analysis of alternative pre-mRNA splicing and RNA-binding specificities of the Drosophila hnRNP A/B family members. Mol. Cell 33:438–49 [Google Scholar]
  136. Venables JP, Koh C-S, Froehlich U, Couture S, Inkle L. 136.  et al. 2008. Multiple and specific mRNA processing targets for the major human hnRNP proteins. Mol. Cell. Biol. 28:6033–43 [Google Scholar]
  137. Abdul-Manan N, O'Malley SM, Williams KR. 137.  1996. Origins of binding specificity of the A1 heterogeneous nuclear ribonucleoprotein. Biochemistry 35:3545–54 [Google Scholar]
  138. Burd CG, Dreyfuss G. 138.  1994. RNA binding specificity of hnRNP A1: significance of hnRNP A1 high-affinity binding sites in pre-mRNA splicing. EMBO J. 13:1197–204 [Google Scholar]
  139. Caputi M, Mayeda A, Krainer AR, Zahler AM. 139.  1999. hnRNP A/B proteins are required for inhibition of HIV-1 pre-mRNA splicing. EMBO J. 18:4060–67 [Google Scholar]
  140. Zhu J, Mayeda A, Krainer AR. 140.  2001. Exon identity established through differential antagonism between exonic splicing silencer-bound hnRNP A1 and enhancer-bound SR proteins. Mol. Cell 8:1351–61 [Google Scholar]
  141. Okunola HL, Krainer AR. 141.  2009. Cooperative-binding and splicing-repressive properties of hnRNP A1. Mol. Cell. Biol. 29:5620–31 [Google Scholar]
  142. Clower CV, Chatterjee D, Wang Z, Cantley LC, Vander Heiden MG, Krainer AR. 142.  2010. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. PNAS 107:1894–99 [Google Scholar]
  143. Blanchette M, Chabot B. 143.  1999. Modulation of exon skipping by high-affinity hnRNP A1–binding sites and by intron elements that repress splice site utilization. EMBO J. 18:1939–52 [Google Scholar]
  144. Martinez-Contreras R, Fisette J-F, Nasim FH, Madden R, Cordeau M, Chabot B. 144.  2006. Intronic binding sites for hnRNP A/B and hnRNP F/H proteins stimulate pre-mRNA splicing. PLOS Biol. 4:e21 [Google Scholar]
  145. Oh HK, Lee E, Jang HN, Lee J, Moon H. 145.  et al. 2013. hnRNP A1 contacts exon 5 to promote exon 6 inclusion of apoptotic Fas gene. Apoptosis 18:825–35 [Google Scholar]
  146. Motta-Mena LB, Heyd F, Lynch KW. 146.  2010. Context-dependent regulatory mechanism of the splicing factor hnRNP L. Mol. Cell 37:223–34 [Google Scholar]
  147. House AE, Lynch KW. 147.  2006. An exonic splicing silencer represses spliceosome assembly after ATP-dependent exon recognition. Nat. Struct. Mol. Biol. 13:937–44 [Google Scholar]
  148. Chiou NT, Shankarling G, Lynch KW. 148.  2013. hnRNP L and hnRNP A1 induce extended U1 snRNA interactions with an exon to repress spliceosome assembly. Mol. Cell 49:972–82 [Google Scholar]
  149. Heiner M, Hui J, Schreiner S, Hung L-H, Bindereif A. 149.  2010. HnRNPL-mediated regulation of mammalian alternative splicing by interference with splice site recognition. RNA Biol. 7:56–64 [Google Scholar]
  150. Rossbach O, Hung L-H, Khrameeva E, Schreiner S, König J. 150.  et al. 2014. Crosslinking-immunoprecipitation (iCLIP) analysis reveals global regulatory roles of hnRNP L. RNA Biol. 11:146–55 [Google Scholar]
  151. Siebel CW, Fresco LD, Rio DC. 151.  1992. The mechanism of somatic inhibition of Drosophila P-element pre-mRNA splicing: multiprotein complexes at an exon pseudo-5′ splice site control U1 snRNP binding. Genes Dev. 6:1386–401 [Google Scholar]
  152. Siebel CW, Rio DC. 152.  1990. Regulated splicing of the Drosophila P transposable element third intron in vitro: somatic repression. Science 248:1200–8 [Google Scholar]
  153. Siebel CW, Kanaar R, Rio DC. 153.  1994. Regulation of tissue-specific P-element pre-mRNA splicing requires the RNA-binding protein PSI. Genes Dev. 8:1713–25 [Google Scholar]
  154. Siebel CW, Admon A, Rio DC. 154.  1995. Soma-specific expression and cloning of PSI, a negative regulator of P element pre-mRNA splicing. Genes Dev. 9:269–83 [Google Scholar]
  155. Tange TO, Damgaard CK, Guth S, Valcárcel J, Kjems J. 155.  2001. The hnRNP A1 protein regulates HIV-1 tat splicing via a novel intron silencer element. EMBO J. 20:5748–58 [Google Scholar]
  156. Damgaard CK, Tange TO, Kjems J. 156.  2002. hnRNP A1 controls HIV-1 mRNA splicing through cooperative binding to intron and exon splicing silencers in the context of a conserved secondary structure. RNA 8:1401–15 [Google Scholar]
  157. Schaal TD, Maniatis T. 157.  1999. Selection and characterization of pre-mRNA splicing enhancers: identification of novel SR protein–specific enhancer sequences. Mol. Cell. Biol. 19:1705–19 [Google Scholar]
  158. Liu HX, Chew SL, Cartengi L, Zhang MQ, Krainer AR. 158.  2000. Exonic splicing enhancer motif recognized by human SC35 under splicing conditions. Mol. Cell. Biol. 20:1063–71 [Google Scholar]
  159. Fairbrother WG, Yeh R-F, Sharp PA, Burge CB. 159.  2002. Predictive identification of exonic splicing enhancers in human genes. Science 297:1007–13 [Google Scholar]
  160. Wang Z, Rolish ME, Yeo G, Tung V, Mawson M, Burge CB. 160.  2004. Systematic identification and analysis of exonic splicing silencers. Cell 119:831–45 [Google Scholar]
  161. Wang Z, Xiao X, Van Nostrand E, Burge CB. 161.  2006. General and specific functions of exonic splicing silencers in splicing control. Mol. Cell 23:61–70 [Google Scholar]
  162. Yu Y, Maroney PA, Denker JA, Zhang XH-F, Dybkov O. 162.  et al. 2008. Dynamic regulation of alternative splicing by silencers that modulate 5′ splice site competition. Cell 135:1224–36 [Google Scholar]
  163. Wang Y, Xiao X, Zhang J, Choudhury R, Robertson A. 163.  et al. 2013. A complex network of factors with overlapping affinities represses splicing through intronic elements. Nat. Struct. Mol. Biol. 20:36–45 [Google Scholar]
  164. Wang Y, Wang Z. 164.  2014. Systematical identification of splicing regulatory cis-elements and cognate trans-factors. Methods 65:350–58 [Google Scholar]
  165. Chabot B, Steitz JA. 165.  1987. Recognition of mutant and cryptic 5′ splice sites by the U1 small nuclear ribonucleoprotein in vitro. Mol. Cell. Biol. 7:698–707 [Google Scholar]
  166. Nelson KK, Green MR. 166.  1988. Splice site selection and ribonucleoprotein complex assembly during in vitro pre-mRNA splicing. Genes Dev. 2:319–29 [Google Scholar]
  167. Berg MG, Singh LN, Younis I, Liu Q, Pinto AM. 167.  et al. 2012. U1 snRNP determines mRNA length and regulates isoform expression. Cell 150:53–64 [Google Scholar]
  168. Kaida D, Berg MG, Younis I, Kasim M, Singh LN. 168.  et al. 2010. U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468:664–68 [Google Scholar]
  169. Labourier E, Adams MD, Rio DC. 169.  2001. Modulation of P-element pre-mRNA splicing by a direct interaction between PSI and U1 snRNP 70K protein. Mol. Cell 8:363–73 [Google Scholar]
  170. Kohtz JD, Jamison SF, Will CL, Zuo P, Lührmann R. 170.  et al. 1994. Protein–protein interactions and 5′-splice-site recognition in mammalian mRNA precursors. Nature 368:119–24 [Google Scholar]
  171. Förch P, Puig O, Martínez C, Séraphin B, Valcárcel J. 171.  2002. The splicing regulator TIA-1 interacts with U1-C to promote U1 snRNP recruitment to 5′ splice sites. EMBO J. 21:6882–92 [Google Scholar]
  172. Du H, Rosbash M. 172.  2002. The U1 snRNP protein U1C recognizes the 5′ splice site in the absence of base pairing. Nature 419:86–90 [Google Scholar]
  173. Sharma S, Maris C, Allain FH-T, Black DL. 173.  2011. U1 snRNA directly interacts with polypyrimidine tract–binding protein during splicing repression. Mol. Cell 41:579–88 [Google Scholar]
  174. Lynch KW, Maniatis T. 174.  1996. Assembly of specific SR protein complexes on distinct regulatory elements of the Drosophila doublesex splicing enhancer. Genes Dev. 10:2089–101 [Google Scholar]
  175. Ohno G, Ono K, Togo M, Watanabe Y, Ono S. 175.  et al. 2012. Muscle-specific splicing factors ASD-2 and SUP-12 cooperatively switch alternative pre-mRNA processing patterns of the ADF/cofilin gene in Caenorhabditis elegans. PLOS Genet. 8:e1002991 [Google Scholar]
  176. Buratti E, Baralle FE. 176.  2004. Influence of RNA secondary structure on the pre-mRNA splicing process. Mol. Cell. Biol. 24:10505–14 [Google Scholar]
  177. McManus CJ, Graveley BR. 177.  2011. RNA structure and the mechanisms of alternative splicing. Curr. Opin. Genet. Dev. 21:373–79 [Google Scholar]
  178. Rouskin S, Zubradt M, Washietl S, Kellis M, Weissman JS. 178.  2014. Genome-wide probing of RNA structure reveals active unfolding of mRNA structures in vivo. Nature 505:701–5 [Google Scholar]
  179. Graveley BR. 179.  2005. Mutually exclusive splicing of the insect Dscam pre-mRNA directed by competing intronic RNA secondary structures. Cell 123:65–73 [Google Scholar]
  180. May GE, Olson S, McManus CJ, Graveley BR. 180.  2011. Competing RNA secondary structures are required for mutually exclusive splicing of the Dscam exon 6 cluster. RNA 17:222–29 [Google Scholar]
  181. Miura SK, Martins A, Zhang KX, Graveley BR, Zipursky SL. 181.  2013. Probabilistic splicing of Dscam1 establishes identity at the level of single neurons. Cell 155:1166–77 [Google Scholar]
  182. Yang Y, Zhan L, Zhang W, Sun F, Wang W. 182.  et al. 2011. RNA secondary structure in mutually exclusive splicing. Nat. Struct. Mol. Biol. 18:159–68 [Google Scholar]
  183. de Almeida SF, Carmo-Fonseca M. 183.  2012. Design principles of interconnections between chromatin and pre-mRNA splicing. Trends Biochem. Sci. 37:248–53 [Google Scholar]
  184. Iannone C, Valcárcel J. 184.  2013. Chromatin's thread to alternative splicing regulation. Chromosoma 122:465–74 [Google Scholar]
  185. de la Mata M, Alonso CR, Kadener S, Fededa JP, Blaustein M. 185.  et al. 2003. A slow RNA polymerase II affects alternative splicing in vivo. Mol. Cell 12:525–32 [Google Scholar]
  186. Sims RJ 3rd, Millhouse S, Chen C-F, Lewis BA, Erdjument-Bromage H. 186.  et al. 2007. Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre-mRNA splicing. Mol. Cell 28:665–76 [Google Scholar]
  187. Luco RF, Pan Q, Tominaga K, Blencowe BJ, Pereira-Smith OM, Misteli T. 187.  2010. Regulation of alternative splicing by histone modifications. Science 327:996–1000 [Google Scholar]
  188. Alló M, Buggiano V, Fededa JP, Petrillo E, Schor I. 188.  et al. 2009. Control of alternative splicing through siRNA-mediated transcriptional gene silencing. Nat. Struct. Mol. Biol. 16:717–24 [Google Scholar]
  189. Johnson JM, Castle J, Garrett-Engele P, Kan Z, Loerch PM. 189.  et al. 2003. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 302:2141–44 [Google Scholar]
  190. Pan Q, Shai O, Misquitta C, Zhang W, Saltzman AL. 190.  et al. 2004. Revealing global regulatory features of mammalian alternative splicing using a quantitative microarray platform. Mol. Cell 16:929–41 [Google Scholar]
  191. Blanchette M, Green RE, Brenner SE, Rio DC. 191.  2005. Global analysis of positive and negative pre-mRNA splicing regulators in Drosophila. Genes Dev. 19:1306–14 [Google Scholar]
  192. Brown V, Jin P, Ceman S, Darnell JC, O'Donnell WT. 192.  et al. 2001. Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell 107:477–87 [Google Scholar]
  193. Labourier E, Blanchette M, Feiger JW, Adams MD, Rio DC. 193.  2002. The KH-type RNA-binding protein PSI is required for Drosophila viability, male fertility, and cellular mRNA processing. Genes Dev. 16:72–84 [Google Scholar]
  194. Mili S, Steitz JA. 194.  2004. Evidence for reassociation of RNA-binding proteins after cell lysis: implications for the interpretation of immunoprecipitation analyses. RNA 10:1692–94 [Google Scholar]
  195. Pawlicki JM, Steitz JA. 195.  2010. Nuclear networking fashions pre-messenger RNA and primary microRNA transcripts for function. Trends Cell Biol. 20:52–61 [Google Scholar]
  196. Ule J, Jensen KB, Ruggiu M, Mele A, Ule A, Darnell RB. 196.  2003. CLIP identifies Nova-regulated RNA networks in the brain. Science 302:1212–15 [Google Scholar]
  197. Choi YD, Dreyfuss G. 197.  1984. Monoclonal antibody characterization of the C proteins of heterogeneous nuclear ribonucleoprotein complexes in vertebrate cells. J. Cell Biol. 99:1997–204 [Google Scholar]
  198. Licatalosi DD, Mele A, Fak JJ, Ule J, Kayikci M. 198.  et al. 2008. HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456:464–69 [Google Scholar]
  199. Sanford JR, Wang X, Mort M, Vanduyn N, Cooper DN. 199.  et al. 2009. Splicing factor SFRS1 recognizes a functionally diverse landscape of RNA transcripts. Genome Res. 19:381–94 [Google Scholar]
  200. Xue Y, Zhou Y, Wu T, Zhu T, Ji X. 200.  et al. 2009. Genome-wide analysis of PTB–RNA interactions reveals a strategy used by the general splicing repressor to modulate exon inclusion or skipping. Mol. Cell 36:996–1006 [Google Scholar]
  201. Huppertz I, Attig J, D'Ambrogio A, Easton LE, Sibley CR. 201.  et al. 2014. iCLIP: protein-RNA interactions at nucleotide resolution. Methods 65:274–87 [Google Scholar]
  202. Hafner M, Landthaler M, Burger L, Khorshid M, Hausser L. 202.  et al. 2010. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141:129–41 [Google Scholar]
  203. Chen J, Zhang Z, Li L, Chen B-C, Revyakin A. 203.  et al. 2014. Single-molecule dynamics of enhanceosome assembly in embryonic stem cells. Cell 156:1274–85 [Google Scholar]
  204. Singh G, Ricci EP, Moore MJ. 204.  2014. RIPiT-seq: a high-throughput approach for footprinting RNA:protein complexes. Methods 65:320–32 [Google Scholar]
  205. Silverman IM, Li F, Alexander A, Goff L, Trapnell C. 205.  et al. 2014. RNase-mediated protein footprint sequencing reveals protein-binding sites throughout the human transcriptome. Genome Biol. 15:R3 [Google Scholar]
  206. Lambert N, Robertson A, Jangi M, McGeary S, Sharp PA, Burge CB. 206.  2014. RNA Bind-n-Seq: quantitative assessment of the sequence and structural binding specificity of RNA binding proteins. Mol. Cell 54:887–900 [Google Scholar]
  207. Ray D, Kazan H, Cook KB, Weirauch MT, Najafabadi HS. 207.  et al. 2013. A compendium of RNA-binding motifs for decoding gene regulation. Nature 499:172–77 [Google Scholar]
  208. Spitale RC, Crisalli P, Flynn RA, Torre EA, Kool ET, Chang HY. 208.  2013. RNA SHAPE analysis in living cells. Nat. Chem. Biol. 9:18–20 [Google Scholar]
  209. Ding Y, Tang Y, Kwok CK, Zhang Y, Bevilacqua PC, Assmann SM. 209.  2014. In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features. Nature 505:696–700 [Google Scholar]
  210. Talkish J, May G, Lin Y, Woolford JL Jr, McManus CJ. 210.  2014. Mod-seq: high-throughput sequencing for chemical probing of RNA structure. RNA 20:713–20 [Google Scholar]
  211. Witten JT, Ule J. 211.  2011. Understanding splicing regulation through RNA splicing maps. Trends Genet. 27:89–97 [Google Scholar]
  212. König J, Zarnack K, Luscombe NM, Ule J. 212.  2011. Protein-RNA interactions: new genomic technologies and perspectives. Nat. Rev. Genet. 13:77–83 [Google Scholar]
  213. Brooks AN, Yang L, Duff MO, Hansen KD, Park JW. 213.  et al. 2011. Conservation of an RNA regulatory map between Drosophila and mammals. Genome Res. 21:193–202 [Google Scholar]
  214. Charizanis K, Lee KY, Batra R, Goodwin M, Zhang C. 214.  et al. 2012. Muscleblind-like 2–mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy. Neuron 75:437–50 [Google Scholar]
  215. Barash Y, Calarco JA, Gao W, Pan Q, Wang X. 215.  et al. 2010. Deciphering the splicing code. Nature 465:53–59 [Google Scholar]
  216. Zhang C, Frias MA, Mele A, Ruggiu M, Eom T. 216.  et al. 2010. Integrative modeling defines the nova splicing-regulatory network and its combinatorial controls. Science 329:439–43 [Google Scholar]
  217. Perales R, Bentley D. 217.  2009. “Cotranscriptionality”: the transcription elongation complex as a nexus for nuclear transactions. Mol. Cell 36:178–91 [Google Scholar]
  218. Lacadie SA, Rosbash M. 218.  2005. Cotranscriptional spliceosome assembly dynamics and the role of U1 snRNA:5′ss base pairing in yeast. Mol. Cell 19:65–75 [Google Scholar]
  219. Görnemann J, Kotovic KM, Hujer K, Neugebauer KM. 219.  2005. Cotranscriptional spliceosome assembly occurs in a stepwise fashion and requires the cap binding complex. Mol. Cell 19:53–63 [Google Scholar]
  220. Listerman I, Sapra AK, Neugebauer KM. 220.  2006. Cotranscriptional coupling of splicing factor recruitment and precursor messenger RNA splicing in mammalian cells. Nat. Struct. Mol. Biol. 13:815–22 [Google Scholar]
  221. Darnell JE Jr. 221.  2013. Reflections on the history of pre-mRNA processing and highlights of current knowledge: a unified picture. RNA 19:443–60 [Google Scholar]
  222. Rodriguez J, Menet JS, Rosbash M. 222.  2012. Nascent-seq indicates widespread cotranscriptional RNA editing in Drosophila. Mol. Cell 47:27–37 [Google Scholar]
  223. Khodor YL, Menet JS, Tolan M, Rosbash M. 223.  2012. Cotranscriptional splicing efficiency differs dramatically between Drosophila and mouse. RNA 18:2174–86 [Google Scholar]
  224. Khodor YL, Rodriguez J, Abruzzi KC, Tang C-HA, Marr MT II, Rosbash M. 224.  2011. Nascent-seq indicates widespread cotranscriptional pre-mRNA splicing in Drosophila. Genes Dev. 25:2502–12 [Google Scholar]
  225. Lacadie SA, Tardiff DF, Kadener S, Rosbash M. 225.  2006. In vivo commitment to yeast cotranscriptional splicing is sensitive to transcription elongation mutants. Genes Dev. 20:2055–66 [Google Scholar]
  226. Carrillo Oesterreich F, Preibisch S, Neugebauer KM. 226.  2010. Global analysis of nascent RNA reveals transcriptional pausing in terminal exons. Mol. Cell 40:571–81 [Google Scholar]
  227. Pandya-Jones A, Black DL. 227.  2009. Co-transcriptional splicing of constitutive and alternative exons. RNA 15:1896–908 [Google Scholar]
  228. Pandya-Jones A, Bhatt DM, Lin C-H, Tong A-J, Smale ST, Black DL. 228.  2013. Splicing kinetics and transcript release from the chromatin compartment limit the rate of lipid A–induced gene expression. RNA 19:811–27 [Google Scholar]
  229. Bhatt DM, Pandya-Jones A, Tong A-J, Barozzi I, Lissner MM. 229.  et al. 2012. Transcript dynamics of proinflammatory genes revealed by sequence analysis of subcellular RNA fractions. Cell 150:279–90 [Google Scholar]
  230. Brugiolo M, Herzel L, Neugebauer KM. 230.  2013. Counting on co-transcriptional splicing. F1000Prime Rep. 5:9 [Google Scholar]
  231. Brody Y, Neufeld N, Bieberstein N, Causse SZ, Böhnlein E-M. 231.  et al. 2011. The in vivo kinetics of RNA polymerase II elongation during co-transcriptional splicing. PLOS Biol. 9:e1000573 [Google Scholar]
  232. Girard C, Will CL, Peng J, Makarov EM, Kastner B. 232.  et al. 2012. Post-transcriptional spliceosomes are retained in nuclear speckles until splicing completion. Nat. Commun. 3:994 [Google Scholar]
  233. Hirose Y, Manley JL. 233.  2000. RNA polymerase II and the integration of nuclear events. Genes Dev. 14:1415–29 [Google Scholar]
  234. Hsin JP, Manley JL. 234.  2012. The RNA polymerase II CTD coordinates transcription and RNA processing. Genes Dev. 26:2119–37 [Google Scholar]
  235. David CJ, Manley JL. 235.  2011. The RNA polymerase C-terminal domain: a new role in spliceosome assembly. Transcription 2:221–25 [Google Scholar]
  236. Hirose Y, Tacke R, Manley JL. 236.  1999. Phosphorylated RNA polymerase II stimulates pre-mRNA splicing. Genes Dev. 13:1234–39 [Google Scholar]
  237. Hirose Y, Manley JL. 237.  1998. RNA polymerase II is an essential mRNA polyadenylation factor. Nature 395:93–96 [Google Scholar]
  238. Das R, Yu J, Zhang Z, Gygi MP, Krainer AR. 238.  et al. 2007. SR proteins function in coupling RNAP II transcription to pre-mRNA splicing. Mol. Cell 26:867–81 [Google Scholar]
  239. Lou H, Gagel RF, Berget SM. 239.  1996. An intron enhancer recognized by splicing factors activates polyadenylation. Genes Dev. 10:208–19 [Google Scholar]
  240. Almada AE, Wu X, Kriz AJ, Burge CB, Sharp PA. 240.  2013. Promoter directionality is controlled by U1 snRNP and polyadenylation signals. Nature 499:360–63 [Google Scholar]
  241. Chi SW, Zang JB, Mele A, Darnell RB. 241.  2009. Argonaute HITS-CLIP decodes microRNA–mRNA interaction maps. Nature 460:479–86 [Google Scholar]
  242. Leung AK, Young AG, Bhutkar A, Zheng GX, Bosson AD. 242.  et al. 2011. Genome-wide identification of Ago2 binding sites from mouse embryonic stem cells with and without mature microRNAs. Nat. Struct. Mol. Biol. 18:237–44 [Google Scholar]
  243. Zisoulis DG, Lovci MT, Wilbert ML, Hutt KR, Liang TY. 243.  et al. 2010. Comprehensive discovery of endogenous Argonaute binding sites in Caenorhabditis elegans. Nat. Struct. Mol. Biol. 17:173–79 [Google Scholar]
  244. Taliaferro JM, Aspden JL, Bradley T, Marwha D, Blanchette M, Rio DC. 244.  2013. Two new and distinct roles for Drosophila Argonaute-2 in the nucleus: alternative pre-mRNA splicing and transcriptional repression. Genes Dev. 27:378–89 [Google Scholar]
  245. Moshkovich N, Nisha P, Boyle PJ, Thompson BA, Dale RK, Lei EP. 245.  2011. RNAi-independent role for Argonaute2 in CTCF/CP190 chromatin insulator function. Genes Dev. 25:1686–701 [Google Scholar]
  246. Cernilogar FM, Onorati MC, Kothe GO, Burroughs AM, Parsi KM. 246.  et al. 2011. Chromatin-associated RNA interference components contribute to transcriptional regulation in Drosophila. Nature 480:391–95 [Google Scholar]
  247. Zamudio JR, Kelly TJ, Sharp PA. 247.  2014. Argonaute-bound small RNAs from promoter-proximal RNA polymerase II. Cell 156:920–34 [Google Scholar]
  248. Ameyar-Zazoua M, Rachez C, Souidi M, Robin P, Fritsch L. 248.  et al. 2012. Argonaute proteins couple chromatin silencing to alternative splicing. Nat. Struct. Mol. Biol. 19:998–1004 [Google Scholar]
  249. Sander B, Golas MM, Makarov EM, Brahms H, Kastner B. 249.  et al. 2006. Organization of core spliceosomal components U5 snRNA loop I and U4/U6 di-snRNP within U4/U6.U5 tri-snRNP as revealed by electron cryomicroscopy. Mol. Cell 24:267–78 [Google Scholar]
  250. Wolf E, Kastner B, Deckert J, Merz C, Stark H, Lührmann R. 250.  2009. Exon, intron and splice site locations in the spliceosomal B complex. EMBO J. 28:2283–92 [Google Scholar]
  251. Kastner B, Lührmann R. 251.  1989. Electron microscopy of U1 small nuclear ribonucleoprotein particles: shape of the particle and position of the 5′ RNA terminus. EMBO J. 8:277–86 [Google Scholar]
  252. Kastner B, Kornstädt U, Bach M, Lührmann R. 252.  1992. Structure of the small nuclear RNP particle U1: identification of the two structural protuberances with RNP-antigens A and 70K. J. Cell Biol. 116:839–49 [Google Scholar]
  253. Burge CB, Tuschl T, Sharp PA. 253.  1999. Splicing of Precurors to mRNAs by the Spliceosome Cold Spring Harbor, NY: Cold Spring Harbor Lab. Press525–60
  254. Padgett RA, Burge CB. 254.  2005. Splice sites. Encyclopedia of Life Sciences1–7 New York: Wiley [Google Scholar]
  255. Graveley BR, Brooks AN, Carlson JW, Duff MO, Landolin JM. 255.  et al. 2011. The developmental transcriptome of Drosophila melanogaster. Nature 471:473–79 [Google Scholar]
  256. Brown JB, Boley N, Eisman R, May GE, Soiber MH. 256.  et al. 2014. Diversity and dynamics of the Drosophila transcriptome. Nature 512:393–99 [Google Scholar]
  257. Ramani AK, Calarco JA, Pan Q, Mavandadi S, Wang Y. 257.  et al. 2011. Genome-wide analysis of alternative splicing in Caenorhabditis elegans. Genome Res. 21:342–48 [Google Scholar]
  258. Kondo Y, Oubridge C, van Roon AM, Nagai K. 258.  2015. Crystal structure of human U1 snRNP, a small nuclear ribonucleoprotein particle, reveals the mechanism of 5′ splice site recognition. eLife 4:e04986 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error