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Diverse regulation of 3′ splice site usage

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Abstract

The regulation of splice site (SS) usage is important for alternative pre-mRNA splicing and thus proper expression of protein isoforms in cells; its disruption causes diseases. In recent years, an increasing number of novel regulatory elements have been found within or nearby the 3′SS in mammalian genes. The diverse elements recruit a repertoire of trans-acting factors or form secondary structures to regulate 3′SS usage, mostly at the early steps of spliceosome assembly. Their mechanisms of action mainly include: (1) competition between the factors for RNA elements, (2) steric hindrance between the factors, (3) direct interaction between the factors, (4) competition between two splice sites, or (5) local RNA secondary structures or longer range loops, according to the mode of protein/RNA interactions. Beyond the 3′SS, chromatin remodeling/transcription, posttranslational modifications of trans-acting factors and upstream signaling provide further layers of regulation. Evolutionarily, some of the 3′SS elements seem to have emerged in mammalian ancestors. Moreover, other possibilities of regulation such as that by non-coding RNA remain to be explored. It is thus likely that there are more diverse elements/factors and mechanisms that influence the choice of an intron end. The diverse regulation likely contributes to a more complex but refined transcriptome and proteome in mammals.

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References

  1. Maniatis T, Tasic B (2002) Alternative pre-mRNA splicing and proteome expansion in metazoans. Nature 418(6894):236–243

    Article  CAS  PubMed  Google Scholar 

  2. Nilsen TW, Graveley BR (2010) Expansion of the eukaryotic proteome by alternative splicing. Nature 463(7280):457–463

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ (2008) Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 40(12):1413–1415

    Article  CAS  PubMed  Google Scholar 

  4. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456(7221):470–476

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Singh RK, Cooper TA (2012) Pre-mRNA splicing in disease and therapeutics. Trends Mol Med 18(8):472–482

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Feng D, Xie J (2013) Aberrant splicing in neurological diseases. Wiley Interdisc Rev RNA 4(6):631–649

    CAS  Google Scholar 

  7. Umen JG, Guthrie C (1995) The second catalytic step of pre-mRNA splicing. RNA 1(9):869–885

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Huang T, Vilardell J, Query CC (2002) Pre-spliceosome formation in S. pombe requires a stable complex of SF1-U2AF(59)-U2AF(23). EMBO J 21(20):5516–5526

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Hollins C, Zorio DA, MacMorris M, Blumenthal T (2005) U2AF binding selects for the high conservation of the C. elegans 3′ splice site. RNA 11(3):248–253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Blumenthal T, Steward K (1997) RNA processing and gene structure. In: Riddle DL, Blumenthal T, Meyer BJ et al (eds) C. elegans II, 2nd edn. Cold Spring Harbor Laboratory Press, New York

    Google Scholar 

  11. Kent WJ, Zahler AM (2000) Conservation, regulation, synteny, and introns in a large-scale C. briggsae–C. elegans genomic alignment. Genome Res 10(8):1115–1125

    Article  CAS  PubMed  Google Scholar 

  12. Reed R (1989) The organization of 3′ splice-site sequences in mammalian introns. Genes Dev 3(12B):2113–2123

    Article  CAS  PubMed  Google Scholar 

  13. Smith CW, Porro EB, Patton JG, Nadal-Ginard B (1989) Scanning from an independently specified branch point defines the 3′ splice site of mammalian introns. Nature 342(6247):243–247

    Article  CAS  PubMed  Google Scholar 

  14. Will CL, Luhrmann R (2011) Spliceosome structure and function. Cold Spring Harbor Perspect Biol 3:a003707. doi:10.1101/cshperspect.a003707

    Article  CAS  Google Scholar 

  15. Berget SM (1995) Exon recognition in vertebrate splicing. J Biol Chem 270(6):2411–2414

    Article  CAS  PubMed  Google Scholar 

  16. Sharma S, Falick AM, Black DL (2005) Polypyrimidine tract binding protein blocks the 5′ splice site-dependent assembly of U2AF and the prespliceosomal E complex. Mol Cell 19(4):485–496

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Sharma S, Kohlstaedt LA, Damianov A, Rio DC, Black DL (2008) Polypyrimidine tract binding protein controls the transition from exon definition to an intron defined spliceosome. Nat Struct Mol Biol 15(2):183–191

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72:291–336

    Article  CAS  PubMed  Google Scholar 

  19. Chen M, Manley JL (2009) Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol 10(11):741–754

    PubMed Central  CAS  PubMed  Google Scholar 

  20. Buratti E, Baralle FE (2004) Influence of RNA secondary structure on the pre-mRNA splicing process. Mol Cell Biol 24(24):10505–10514

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Wu T, Fu XD (2015) Genomic functions of U2AF in constitutive and regulated splicing. RNA Biol 12(5):479–485

    Article  PubMed  Google Scholar 

  22. Shao C, Yang B, Wu T, Huang J, Tang P, Zhou Y, Zhou J, Qiu J, Jiang L, Li H et al (2014) Mechanisms for U2AF to define 3′ splice sites and regulate alternative splicing in the human genome. Nat Struct Mol Biol 21(11):997–1005

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Saltzman AL, Pan Q, Blencowe BJ (2011) Regulation of alternative splicing by the core spliceosomal machinery. Genes Dev 25(4):373–384

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Rosel TD, Hung LH, Medenbach J, Donde K, Starke S, Benes V, Ratsch G, Bindereif A (2011) RNA-Seq analysis in mutant zebrafish reveals role of U1C protein in alternative splicing regulation. EMBO J 30(10):1965–1976

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Sauliere J, Sureau A, Expert-Bezancon A, Marie J (2006) The polypyrimidine tract binding protein (PTB) represses splicing of exon 6B from the beta-tropomyosin pre-mRNA by directly interfering with the binding of the U2AF65 subunit. Mol Cell Biol 26(23):8755–8769

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Gooding C, Roberts GC, Moreau G, Nadal-Ginard B, Smith CW (1994) Smooth muscle-specific switching of alpha-tropomyosin mutually exclusive exon selection by specific inhibition of the strong default exon. EMBO J 13(16):3861–3872

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Perez I, Lin CH, McAfee JG, Patton JG (1997) Mutation of PTB binding sites causes misregulation of alternative 3′ splice site selection in vivo. RNA 3(7):764–778

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Smith CW, Nadal-Ginard B (1989) Mutually exclusive splicing of alpha-tropomyosin exons enforced by an unusual lariat branch point location: implications for constitutive splicing. Cell 56(5):749–758

    Article  CAS  PubMed  Google Scholar 

  29. Chan RC, Black DL (1997) The polypyrimidine tract binding protein binds upstream of neural cell-specific c-src exon N1 to repress the splicing of the intron downstream. Mol Cell Biol 17(8):4667–4676

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Chou MY, Underwood JG, Nikolic J, Luu MH, Black DL (2000) Multisite RNA binding and release of polypyrimidine tract binding protein during the regulation of c-src neural-specific splicing. Mol Cell 5(6):949–957

    Article  CAS  PubMed  Google Scholar 

  31. Matlin AJ, Southby J, Gooding C, Smith CW (2007) Repression of alpha-actinin SM exon splicing by assisted binding of PTB to the polypyrimidine tract. RNA 13(8):1214–1223

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Southby J, Gooding C, Smith CW (1999) Polypyrimidine tract binding protein functions as a repressor to regulate alternative splicing of alpha-actinin mutually exclusive exons. Mol Cell Biol 19(4):2699–2711

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Zhang L, Liu W, Grabowski PJ (1999) Coordinate repression of a trio of neuron-specific splicing events by the splicing regulator PTB. RNA (New York) 5(1):117–130

    Article  PubMed Central  CAS  Google Scholar 

  34. Raj B, Irimia M, Braunschweig U, Sterne-Weiler T, O’Hanlon D, Lin ZY, Chen GI, Easton LE, Ule J, Gingras AC et al (2014) A global regulatory mechanism for activating an exon network required for neurogenesis. Mol Cell 56(1):90–103

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Singh R, Banerjee H, Green MR (2000) Differential recognition of the polypyrimidine-tract by the general splicing factor U2AF65 and the splicing repressor sex-lethal. RNA 6(6):901–911

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Valcarcel J, Singh R, Zamore PD, Green MR (1993) The protein Sex-lethal antagonizes the splicing factor U2AF to regulate alternative splicing of transformer pre-mRNA. Nature 362(6416):171–175

    Article  CAS  PubMed  Google Scholar 

  37. Lisbin MJ, Qiu J, White K (2001) The neuron-specific RNA-binding protein ELAV regulates neuroglian alternative splicing in neurons and binds directly to its pre-mRNA. Genes Dev 15(19):2546–2561

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Anyanful A, Ono K, Johnsen RC, Ly H, Jensen V, Baillie DL, Ono S (2004) The RNA-binding protein SUP-12 controls muscle-specific splicing of the ADF/cofilin pre-mRNA in C. elegans. J Cell Biol 167(4):639–647

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Ayala YM, Pagani F, Baralle FE (2006) TDP43 depletion rescues aberrant CFTR exon 9 skipping. FEBS Lett 580(5):1339–1344

    Article  CAS  PubMed  Google Scholar 

  40. Buratti E, Dork T, Zuccato E, Pagani F, Romano M, Baralle FE (2001) Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J 20(7):1774–1784

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Ho TH, Charlet BN, Poulos MG, Singh G, Swanson MS, Cooper TA (2004) Muscleblind proteins regulate alternative splicing. EMBO J 23(15):3103–3112

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Warf MB, Diegel JV, von Hippel PH, Berglund JA (2009) The protein factors MBNL1 and U2AF65 bind alternative RNA structures to regulate splicing. Proc Natl Acad Sci USA 106(23):9203–9208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Cao W, Razanau A, Feng D, Lobo VG, Xie J (2012) Control of alternative splicing by forskolin through hnRNP K during neuronal differentiation. Nucleic Acids Res 40(16):8059–8071

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Zarnack K, Konig J, Tajnik M, Martincorena I, Eustermann S, Stevant I, Reyes A, Anders S, Luscombe NM, Ule J (2013) Direct competition between hnRNP C and U2AF65 protects the transcriptome from the exonization of Alu elements. Cell 152(3):453–466

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Loh TJ, Cho S, Moon H, Jang HN, Williams DR, Jung DW, Kim IC, Ghigna C, Biamonti G, Zheng X et al. (2015) hnRNP L inhibits CD44 V10 exon splicing through interacting with its upstream intron. Biochim Biophys Acta 1849(6):743–750

    Article  CAS  PubMed  Google Scholar 

  46. Liu G, Razanau A, Hai Y, Yu J, Sohail M, Lobo VG, Chu J, Kung SK, Xie J (2012) A conserved serine of heterogeneous nuclear ribonucleoprotein L (hnRNP L) mediates depolarization-regulated alternative splicing of potassium channels. J Biol Chem 287(27):22709–22716

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Xie J, Jan C, Stoilov P, Park J, Black DL (2005) A consensus CaMK IV-responsive RNA sequence mediates regulation of alternative exons in neurons. RNA 11(12):1825–1834

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Yu J, Hai Y, Liu G, Fang T, Kung SK, Xie J (2009) The heterogeneous nuclear ribonucleoprotein L is an essential component in the Ca2+/calmodulin-dependent protein kinase IV-regulated alternative splicing through cytidine-adenosine repeats. J Biol Chem 284(3):1505–1513

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Heiner M, Hui J, Schreiner S, Hung LH, Bindereif A (2010) HnRNP L-mediated regulation of mammalian alternative splicing by interference with splice site recognition. RNA Biol 7(1):56–64

    Article  CAS  PubMed  Google Scholar 

  50. Sohail M, Xie J (2015) Evolutionary emergence of a novel splice variant with an opposite effect on the cell cycle. Mol Cell Biol 35(12):2203–2214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sohail M, Cao W, Mahmood N, Myschyshyn M, Hong SP, Xie J (2014) Evolutionarily emerged G tracts between the polypyrimidine tract and 3′AG are splicing silencers enriched in genes involved in cancer. BMC Genom 15:1143

    Article  Google Scholar 

  52. Tange TO, Damgaard CK, Guth S, Valcarcel J, Kjems J (2001) The hnRNP A1 protein regulates HIV-1 tat splicing via a novel intron silencer element. EMBO J 20(20):5748–5758

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Dembowski JA, Grabowski PJ (2009) The CUGBP2 splicing factor regulates an ensemble of branchpoints from perimeter binding sites with implications for autoregulation. PLoS Genet 5(8):e1000595

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  54. Zong FY, Fu X, Wei WJ, Luo YG, Heiner M, Cao LJ, Fang Z, Fang R, Lu D, Ji H et al (2014) The RNA-binding protein QKI suppresses cancer-associated aberrant splicing. PLoS Genet 10(4):e1004289

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  55. Corsini L, Bonnal S, Basquin J, Hothorn M, Scheffzek K, Valcarcel J, Sattler M (2007) U2AF-homology motif interactions are required for alternative splicing regulation by SPF45. Nat Struct Mol Biol 14(7):620–629

    Article  CAS  PubMed  Google Scholar 

  56. Taliaferro JM, Alvarez N, Green RE, Blanchette M, Rio DC (2011) Evolution of a tissue-specific splicing network. Genes Dev 25(6):608–620

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Buratti E, Stuani C, De Prato G, Baralle FE (2007) SR protein-mediated inhibition of CFTR exon 9 inclusion: molecular characterization of the intronic splicing silencer. Nucleic Acids Res 35(13):4359–4368

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Wang J, Bell LR (1994) The Sex-lethal amino terminus mediates cooperative interactions in RNA binding and is essential for splicing regulation. Genes Dev 8(17):2072–2085

    Article  CAS  PubMed  Google Scholar 

  59. Horabin JI, Schedl P (1993) Sex-lethal autoregulation requires multiple cis-acting elements upstream and downstream of the male exon and appears to depend largely on controlling the use of the male exon 5′ splice site. Mol Cell Biol 13(12):7734–7746

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Sakamoto H, Inoue K, Higuchi I, Ono Y, Shimura Y (1992) Control of Drosophila Sex-lethal pre-mRNA splicing by its own female-specific product. Nucleic Acids Res 20(21):5533–5540

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Konig J, Zarnack K, Rot G, Curk T, Kayikci M, Zupan B, Turner DJ, Luscombe NM, Ule J (2010) iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol 17(7):909–915

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  62. Gromak N, Matlin AJ, Cooper TA, Smith CW (2003) Antagonistic regulation of alpha-actinin alternative splicing by CELF proteins and polypyrimidine tract binding protein. RNA 9(4):443–456

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Charlet BN, Logan P, Singh G, Cooper TA (2002) Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing. Mol Cell 9(3):649–658

    Article  Google Scholar 

  64. Soares LM, Zanier K, Mackereth C, Sattler M, Valcarcel J (2006) Intron removal requires proofreading of U2AF/3′ splice site recognition by DEK. Science 312(5782):1961–1965

    Article  PubMed  CAS  Google Scholar 

  65. Dowhan DH, Hong EP, Auboeuf D, Dennis AP, Wilson MM, Berget SM, O’Malley BW (2005) Steroid hormone receptor coactivation and alternative RNA splicing by U2AF65-related proteins CAPERalpha and CAPERbeta. Mol Cell 17(3):429–439

    Article  CAS  PubMed  Google Scholar 

  66. Huang G, Zhou Z, Wang H, Kleinerman ES (2012) CAPER-alpha alternative splicing regulates the expression of vascular endothelial growth factor(1)(6)(5) in Ewing sarcoma cells. Cancer 118(8):2106–2116

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Tavanez JP, Madl T, Kooshapur H, Sattler M, Valcarcel J (2012) hnRNP A1 proofreads 3′ splice site recognition by U2AF. Mol Cell 45(3):314–329

    Article  CAS  PubMed  Google Scholar 

  68. Wei WJ, Mu SR, Heiner M, Fu X, Cao LJ, Gong XF, Bindereif A, Hui J (2012) YB-1 binds to CAUC motifs and stimulates exon inclusion by enhancing the recruitment of U2AF to weak polypyrimidine tracts. Nucleic Acids Res 40(17):8622–8636

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Shen H, Zheng X, Luecke S, Green MR (2010) 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. Genes Dev 24(21):2389–2394

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Tisserant A, Konig H (2008) Signal-regulated Pre-mRNA occupancy by the general splicing factor U2AF. PLoS ONE 3(1):e1418

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  71. Shen H, Green MR (2006) RS domains contact splicing signals and promote splicing by a common mechanism in yeast through humans. Genes Dev 20(13):1755–1765

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Shen H, Kan JL, Green MR (2004) Arginine-serine-rich domains bound at splicing enhancers contact the branchpoint to promote prespliceosome assembly. Mol Cell 13(3):367–376

    Article  CAS  PubMed  Google Scholar 

  73. Xue Y, Zhou Y, Wu T, Zhu T, Ji X, Kwon YS, Zhang C, Yeo G, Black DL, Sun H 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(6):996–1006

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Olson S, Blanchette M, Park J, Savva Y, Yeo GW, Yeakley JM, Rio DC, Graveley BR (2007) A regulator of Dscam mutually exclusive splicing fidelity. Nat Struct Mol Biol 14(12):1134–1140

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. May GE, Olson S, McManus CJ, Graveley BR (2011) Competing RNA secondary structures are required for mutually exclusive splicing of the Dscam exon 6 cluster. RNA 17(2):222–229

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Graveley BR (2005) Mutually exclusive splicing of the insect Dscam pre-mRNA directed by competing intronic RNA secondary structures. Cell 123(1):65–73

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Wu JY, Maniatis T (1993) Specific interactions between proteins implicated in splice site selection and regulated alternative splicing. Cell 75(6):1061–1070

    Article  CAS  PubMed  Google Scholar 

  78. Fu XD, Maniatis T (1992) The 35-kDa mammalian splicing factor SC35 mediates specific interactions between U1 and U2 small nuclear ribonucleoprotein particles at the 3′ splice site. Proc Natl Acad Sci USA 89(5):1725–1729

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Hertel KJ, Maniatis T (1998) The function of multisite splicing enhancers. Mol Cell 1(3):449–455

    Article  CAS  PubMed  Google Scholar 

  80. Graveley BR, Hertel KJ, Maniatis T (1998) A systematic analysis of the factors that determine the strength of pre-mRNA splicing enhancers. EMBO J 17(22):6747–6756

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Nasim FU, Hutchison S, Cordeau M, Chabot B (2002) High-affinity hnRNP A1 binding sites and duplex-forming inverted repeats have similar effects on 5′ splice site selection in support of a common looping out and repression mechanism. RNA 8(8):1078–1089

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Chabot B, Blanchette M, Lapierre I, La Branche H (1997) An intron element modulating 5′ splice site selection in the hnRNP A1 pre-mRNA interacts with hnRNP A1. Mol Cell Biol 17(4):1776–1786

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Blanchette M, Chabot B (1999) Modulation of exon skipping by high-affinity hnRNP A1-binding sites and by intron elements that repress splice site utilization. EMBO J 18(7):1939–1952

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Martinez-Contreras R, Fisette JF, Nasim FU, Madden R, Cordeau M, Chabot B (2006) Intronic binding sites for hnRNP A/B and hnRNP F/H proteins stimulate pre-mRNA splicing. PLoS Biol 4(2):e21

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  85. Mulligan GJ, Guo W, Wormsley S, Helfman DM (1992) Polypyrimidine tract binding protein interacts with sequences involved in alternative splicing of beta-tropomyosin pre-mRNA. J Biol Chem 267(35):25480–25487

    CAS  PubMed  Google Scholar 

  86. Singh R, Valcarcel J, Green MR (1995) Distinct binding specificities and functions of higher eukaryotic polypyrimidine tract-binding proteins. Science 268(5214):1173–1176

    Article  CAS  PubMed  Google Scholar 

  87. Li H, Liu G, Yu J, Cao W, Lobo VG, Xie J (2009) In vivo selection of kinase-responsive RNA elements controlling alternative splicing. J Biol Chem 284(24):16191–16201

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Caputi M, Zahler AM (2001) Determination of the RNA binding specificity of the heterogeneous nuclear ribonucleoprotein (hnRNP) H/H′/F/2H9 family. J Biol Chem 276(47):43850–43859

    Article  CAS  PubMed  Google Scholar 

  89. Dominguez C, Allain FH (2006) NMR structure of the three quasi RNA recognition motifs (qRRMs) of human hnRNP F and interaction studies with Bcl-x G-tract RNA: a novel mode of RNA recognition. Nucleic Acids Res 34(13):3634–3645

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Garneau D, Revil T, Fisette JF, Chabot B (2005) Heterogeneous nuclear ribonucleoprotein F/H proteins modulate the alternative splicing of the apoptotic mediator Bcl-x. J Biol Chem 280(24):22641–22650

    Article  CAS  PubMed  Google Scholar 

  91. Chou MY, Rooke N, Turck CW, Black DL (1999) hnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells. Mol Cell Biol 19(1):69–77

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Schaub MC, Lopez SR, Caputi M (2007) Members of the heterogeneous nuclear ribonucleoprotein H family activate splicing of an HIV-1 splicing substrate by promoting formation of ATP-dependent spliceosomal complexes. J Biol Chem 282(18):13617–13626

    Article  CAS  PubMed  Google Scholar 

  93. Wang E, Dimova N, Cambi F (2007) PLP/DM20 ratio is regulated by hnRNPH and F and a novel G-rich enhancer in oligodendrocytes. Nucleic Acids Res 35(12):4164–4178

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Zamore PD, Green MR (1989) Identification, purification, and biochemical characterization of U2 small nuclear ribonucleoprotein auxiliary factor. Proc Natl Acad Sci USA 86(23):9243–9247

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Moore MJ (2000) Intron recognition comes of AGe. Nature structural biology 7(1):14–16

    Article  CAS  PubMed  Google Scholar 

  96. Merendino L, Guth S, Bilbao D, Martinez C, Valcarcel J (1999) Inhibition of msl-2 splicing by Sex-lethal reveals interaction between U2AF35 and the 3′ splice site AG. Nature 402(6763):838–841

    Article  CAS  PubMed  Google Scholar 

  97. Zorio DA, Blumenthal T (1999) Both subunits of U2AF recognize the 3′ splice site in Caenorhabditis elegans. Nature 402(6763):835–838

    Article  CAS  PubMed  Google Scholar 

  98. Wu S, Romfo CM, Nilsen TW, Green MR (1999) Functional recognition of the 3′ splice site AG by the splicing factor U2AF35. Nature 402(6763):832–835

    Article  CAS  PubMed  Google Scholar 

  99. Smith CW, Chu TT, Nadal-Ginard B (1993) Scanning and competition between AGs are involved in 3′ splice site selection in mammalian introns. Mol Cell Biol 13(8):4939–4952

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Kanopka A, Muhlemann O, Akusjarvi G (1996) Inhibition by SR proteins of splicing of a regulated adenovirus pre-mRNA. Nature 381(6582):535–538

    Article  CAS  PubMed  Google Scholar 

  101. Moriyoshi K, Masu M, Ishii T, Shigemoto R, Mizuno N, Nakanishi S (1991) Molecular cloning and characterization of the rat NMDA receptor. Nature 354(6348):31–37

    Article  CAS  PubMed  Google Scholar 

  102. Ladd AN, Charlet N, Cooper TA (2001) The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Mol Cell Biol 21(4):1285–1296

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. Faustino NA, Cooper TA (2005) Identification of putative new splicing targets for ETR-3 using sequences identified by systematic evolution of ligands by exponential enrichment. Mol Cell Biol 25(3):879–887

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Suzuki H, Takeuchi M, Sugiyama A, Alam AK, Vu LT, Sekiyama Y, Dam HC, Ohki SY, Tsukahara T (2012) Alternative splicing produces structural and functional changes in CUGBP2. BMC Biochem 13:6

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  105. Philips AV, Timchenko LT, Cooper TA (1998) Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280(5364):737–741

    Article  CAS  PubMed  Google Scholar 

  106. Timchenko LT, Miller JW, Timchenko NA, DeVore DR, Datar KV, Lin L, Roberts R, Caskey CT, Swanson MS (1996) Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. Nucleic Acids Res 24(22):4407–4414

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Kim-Ha J, Kerr K, Macdonald PM (1995) Translational regulation of oskar mRNA by bruno, an ovarian RNA-binding protein, is essential. Cell 81(3):403–412

    Article  CAS  PubMed  Google Scholar 

  108. Suzuki H, Jin Y, Otani H, Yasuda K, Inoue K (2002) Regulation of alternative splicing of alpha-actinin transcript by Bruno-like proteins. Genes Cells 7(2):133–141

    Article  CAS  PubMed  Google Scholar 

  109. Paillard L, Omilli F, Legagneux V, Bassez T, Maniey D, Osborne HB (1998) EDEN and EDEN-BP, a cis element and an associated factor that mediate sequence-specific mRNA deadenylation in Xenopus embryos. EMBO J 17(1):278–287

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  110. Timchenko NA, Welm AL, Lu X, Timchenko LT (1999) CUG repeat binding protein (CUGBP1) interacts with the 5′ region of C/EBPbeta mRNA and regulates translation of C/EBPbeta isoforms. Nucleic Acids Res 27(22):4517–4525

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Tsuda K, Kuwasako K, Takahashi M, Someya T, Inoue M, Terada T, Kobayashi N, Shirouzu M, Kigawa T, Tanaka A et al (2009) Structural basis for the sequence-specific RNA-recognition mechanism of human CUG-BP1 RRM3. Nucleic Acids Res 37(15):5151–5166

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Guo M, Jan LY, Jan YN (1996) Control of daughter cell fates during asymmetric division: interaction of Numb and Notch. Neuron 17(1):27–41

    Article  PubMed  Google Scholar 

  113. Pece S, Serresi M, Santolini E, Capra M, Hulleman E, Galimberti V, Zurrida S, Maisonneuve P, Viale G, Di Fiore PP (2004) Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 167(2):215–221

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Spana EP, Doe CQ (1996) Numb antagonizes Notch signaling to specify sibling neuron cell fates. Neuron 17(1):21–26

    Article  CAS  PubMed  Google Scholar 

  115. Feng Y, Bankston A (2010) The star family member QKI and cell signaling. Adv Exp Med Biol 693:25–36

    Article  CAS  PubMed  Google Scholar 

  116. Galarneau A, Richard S (2005) Target RNA motif and target mRNAs of the Quaking STAR protein. Nat Struct Mol Biol 12(8):691–698

    Article  CAS  PubMed  Google Scholar 

  117. Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P, Rothballer A, Ascano M Jr, Jungkamp AC, Munschauer M et al (2010) Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141(1):129–141

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. Corioni M, Antih N, Tanackovic G, Zavolan M, Kramer A (2011) Analysis of in situ pre-mRNA targets of human splicing factor SF1 reveals a function in alternative splicing. Nucleic Acids Res 39(5):1868–1879

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Lallena MJ, Chalmers KJ, Llamazares S, Lamond AI, Valcarcel J (2002) Splicing regulation at the second catalytic step by Sex-lethal involves 3′ splice site recognition by SPF45. Cell 109(3):285–296

    Article  CAS  PubMed  Google Scholar 

  120. Graveley BR, Maniatis T (1998) Arginine/serine-rich domains of SR proteins can function as activators of pre-mRNA splicing. Mol Cell 1(5):765–771

    Article  CAS  PubMed  Google Scholar 

  121. Pandit S, Zhou Y, Shiue L, Coutinho-Mansfield G, Li H, Qiu J, Huang J, Yeo GW, Ares M Jr, Fu XD (2013) Genome-wide analysis reveals SR protein cooperation and competition in regulated splicing. Mol Cell 50(2):223–235

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Wang J, Smith PJ, Krainer AR, Zhang MQ (2005) Distribution of SR protein exonic splicing enhancer motifs in human protein-coding genes. Nucleic Acids Res 33(16):5053–5062

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Anko ML, Muller-McNicoll M, Brandl H, Curk T, Gorup C, Henry I, Ule J, Neugebauer KM (2012) The RNA-binding landscapes of two SR proteins reveal unique functions and binding to diverse RNA classes. Genome Biol 13(3):R17

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  124. Erkelenz S, Mueller WF, Evans MS, Busch A, Schoneweis K, Hertel KJ, Schaal H (2013) Position-dependent splicing activation and repression by SR and hnRNP proteins rely on common mechanisms. RNA 19(1):96–102

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Simard MJ, Chabot B (2002) SRp30c is a repressor of 3′ splice site utilization. Mol Cell Biol 22(12):4001–4010

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Fu XD, Mayeda A, Maniatis T, Krainer AR (1992) General splicing factors SF2 and SC35 have equivalent activities in vitro, and both affect alternative 5′ and 3′ splice site selection. Proc Natl Acad Sci USA 89(23):11224–11228

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  127. Gallego ME, Gattoni R, Stevenin J, Marie J, Expert-Bezancon A (1997) The SR splicing factors ASF/SF2 and SC35 have antagonistic effects on intronic enhancer-dependent splicing of the beta-tropomyosin alternative exon 6A. EMBO J 16(7):1772–1784

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  128. Jumaa H, Nielsen PJ (1997) The splicing factor SRp20 modifies splicing of its own mRNA and ASF/SF2 antagonizes this regulation. EMBO J 16(16):5077–5085

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. Solnick D (1985) Alternative splicing caused by RNA secondary structure. Cell 43(3 Pt 2):667–676

    Article  CAS  PubMed  Google Scholar 

  130. Clouet d’Orval B, d’Aubenton Carafa Y, Sirand-Pugnet P, Gallego M, Brody E, Marie J (1991) RNA secondary structure repression of a muscle-specific exon in HeLa cell nuclear extracts. Science 252(5014):1823–1828

    Article  PubMed  Google Scholar 

  131. Chebli K, Gattoni R, Schmitt P, Hildwein G, Stevenin J (1989) The 216-nucleotide intron of the E1A pre-mRNA contains a hairpin structure that permits utilization of unusually distant branch acceptors. Mol Cell Biol 9(11):4852–4861

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  132. Eperon LP, Graham IR, Griffiths AD, Eperon IC (1988) Effects of RNA secondary structure on alternative splicing of pre-mRNA: is folding limited to a region behind the transcribing RNA polymerase? Cell 54(3):393–401

    Article  CAS  PubMed  Google Scholar 

  133. Shepard PJ, Hertel KJ (2008) Conserved RNA secondary structures promote alternative splicing. RNA 14(8):1463–1469

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  134. Zhang J, Kuo CC, Chen L (2011) GC content around splice sites affects splicing through pre-mRNA secondary structures. BMC Genom 12:90

    Article  CAS  Google Scholar 

  135. Meyer M, Plass M, Perez-Valle J, Eyras E, Vilardell J (2011) Deciphering 3′SS selection in the yeast genome reveals an RNA thermosensor that mediates alternative splicing. Mol Cell 43(6):1033–1039

    Article  CAS  PubMed  Google Scholar 

  136. Hiller M, Zhang Z, Backofen R, Stamm S (2007) Pre-mRNA secondary structures influence exon recognition. PLoS Genet 3(11):e204

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  137. Monie TP, Hernandez H, Robinson CV, Simpson P, Matthews S, Curry S (2005) The polypyrimidine tract binding protein is a monomer. RNA 11(12):1803–1808

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  138. Oberstrass FC, Auweter SD, Erat M, Hargous Y, Henning A, Wenter P, Reymond L, Amir-Ahmady B, Pitsch S, Black DL et al (2005) Structure of PTB bound to RNA: specific binding and implications for splicing regulation. Science 309(5743):2054–2057

    Article  CAS  PubMed  Google Scholar 

  139. Kim JH, Hahm B, Kim YK, Choi M, Jang SK (2000) Protein-protein interaction among hnRNPs shuttling between nucleus and cytoplasm. J Mol Biol 298(3):395–405

    Article  CAS  PubMed  Google Scholar 

  140. Rahman MA, Masuda A, Ohe K, Ito M, Hutchinson DO, Mayeda A, Engel AG, Ohno K (2013) HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA. Sci Rep 3:2931

    Article  PubMed Central  PubMed  Google Scholar 

  141. Mollet I, Barbosa-Morais NL, Andrade J, Carmo-Fonseca M (2006) Diversity of human U2AF splicing factors. FEBS J 273(21):4807–4816

    Article  CAS  PubMed  Google Scholar 

  142. Rooke N, Markovtsov V, Cagavi E, Black DL (2003) Roles for SR proteins and hnRNP A1 in the regulation of c-src exon N1. Mol Cell Biol 23(6):1874–1884

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  143. Tronchere H, Wang J, Fu XD (1997) A protein related to splicing factor U2AF35 that interacts with U2AF65 and SR proteins in splicing of pre-mRNA. Nature 388(6640):397–400

    Article  CAS  PubMed  Google Scholar 

  144. Shepard J, Reick M, Olson S, Graveley BR (2002) Characterization of U2AF(6), a splicing factor related to U2AF(35). Mol Cell Biol 22(1):221–230

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  145. Liu Y, Conaway L, Rutherford Bethard J, Al-Ayoubi AM, Thompson Bradley A, Zheng H, Weed SA, Eblen ST (2013) Phosphorylation of the alternative mRNA splicing factor 45 (SPF45) by Clk1 regulates its splice site utilization, cell migration and invasion. Nucleic Acids Res 41(9):4949–4962

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  146. Gahura O, Hammann C, Valentova A, Puta F, Folk P (2011) Secondary structure is required for 3′ splice site recognition in yeast. Nucleic Acids Res 39(22):9759–9767

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  147. Deshler JO, Rossi JJ (1991) Unexpected point mutations activate cryptic 3′ splice sites by perturbing a natural secondary structure within a yeast intron. Genes Dev 5(7):1252–1263

    Article  CAS  PubMed  Google Scholar 

  148. Charpentier B, Rosbash M (1996) Intramolecular structure in yeast introns aids the early steps of in vitro spliceosome assembly. RNA 2(6):509–522

    PubMed Central  CAS  PubMed  Google Scholar 

  149. Luco RF, Pan Q, Tominaga K, Blencowe BJ, Pereira-Smith OM, Misteli T (2010) Regulation of alternative splicing by histone modifications. Science 327(5968):996–1000

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  150. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325(5942):834–840

    Article  CAS  PubMed  Google Scholar 

  151. Ip JY, Schmidt D, Pan Q, Ramani AK, Fraser AG, Odom DT, Blencowe BJ (2011) Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation. Genome Res 21(3):390–401

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  152. de la Mata M, Alonso CR, Kadener S, Fededa JP, Blaustein M, Pelisch F, Cramer P, Bentley D, Kornblihtt AR (2003) A slow RNA polymerase II affects alternative splicing in vivo. Mol Cell 12(2):525–532

    Article  PubMed  Google Scholar 

  153. Roberts GC, Gooding C, Mak HY, Proudfoot NJ, Smith CW (1998) Co-transcriptional commitment to alternative splice site selection. Nucleic Acids Res 26(24):5568–5572

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  154. Fong N, Kim H, Zhou Y, Ji X, Qiu J, Saldi T, Diener K, Jones K, Fu XD, Bentley DL (2014) Pre-mRNA splicing is facilitated by an optimal RNA polymerase II elongation rate. Genes Dev 28(23):2663–2676

    Article  PubMed Central  PubMed  Google Scholar 

  155. Chen W, Luo L, Zhang L (2010) The organization of nucleosomes around splice sites. Nucleic Acids Res 38(9):2788–2798

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  156. Huang H, Yu S, Liu H, Sun X (2012) Nucleosome organization in sequences of alternative events in human genome. Biosystems 109(2):214–219

    Article  CAS  PubMed  Google Scholar 

  157. Reisman DN, Strobeck MW, Betz BL, Sciariotta J, Funkhouser W Jr, Murchardt C, Yaniv M, Sherman LS, Knudsen ES, Weissman BE (2002) Concomitant down-regulation of BRM and BRG1 in human tumor cell lines: differential effects on RB-mediated growth arrest vs CD44 expression. Oncogene 21(8):1196–1207

    Article  CAS  PubMed  Google Scholar 

  158. Kadam S, Emerson BM (2003) Transcriptional specificity of human SWI/SNF BRG1 and BRM chromatin remodeling complexes. Mol Cell 11(2):377–389

    Article  CAS  PubMed  Google Scholar 

  159. Corey LL, Weirich CS, Benjamin IJ, Kingston RE (2003) Localized recruitment of a chromatin-remodeling activity by an activator in vivo drives transcriptional elongation. Genes Dev 17(11):1392–1401

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  160. Batsche E, Yaniv M, Muchardt C (2006) The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nat Struct Mol Biol 13(1):22–29

    Article  CAS  PubMed  Google Scholar 

  161. Matter N, Herrlich P, Konig H (2002) Signal-dependent regulation of splicing via phosphorylation of Sam68. Nature 420(6916):691–695

    Article  CAS  PubMed  Google Scholar 

  162. Webby CJ, Wolf A, Gromak N, Dreger M, Kramer H, Kessler B, Nielsen ML, Schmitz C, Butler DS, Yates JR 3rd et al (2009) Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science 325(5936):90–93

    Article  CAS  PubMed  Google Scholar 

  163. Zhang Y, Madl T, Bagdiul I, Kern T, Kang HS, Zou P, Mausbacher N, Sieber SA, Kramer A, Sattler M (2013) Structure, phosphorylation and U2AF65 binding of the N-terminal domain of splicing factor 1 during 3′-splice site recognition. Nucleic Acids Res 41(2):1343–1354

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  164. Wang X, Bruderer S, Rafi Z, Xue J, Milburn PJ, Kramer A, Robinson PJ (1999) Phosphorylation of splicing factor SF1 on Ser20 by cGMP-dependent protein kinase regulates spliceosome assembly. EMBO J 18(16):4549–4559

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  165. Manceau V, Swenson M, Le Caer JP, Sobel A, Kielkopf CL, Maucuer A (2006) Major phosphorylation of SF1 on adjacent Ser-Pro motifs enhances interaction with U2AF65. FEBS J 273(3):577–587

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  166. Rain JC, Rafi Z, Rhani Z, Legrain P, Kramer A (1998) Conservation of functional domains involved in RNA binding and protein-protein interactions in human and Saccharomyces cerevisiae pre-mRNA splicing factor SF1. RNA 4(5):551–565

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  167. Bezzi M, Teo SX, Muller J, Mok WC, Sahu SK, Vardy LA, Bonday ZQ, Guccione E (2013) Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery. Genes Dev 27(17):1903–1916

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  168. Edmond V, Moysan E, Khochbin S, Matthias P, Brambilla C, Brambilla E, Gazzeri S, Eymin B (2011) Acetylation and phosphorylation of SRSF2 control cell fate decision in response to cisplatin. EMBO J 30(3):510–523

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  169. Kuhn AN, van Santen MA, Schwienhorst A, Urlaub H, Luhrmann R (2009) Stalling of spliceosome assembly at distinct stages by small-molecule inhibitors of protein acetylation and deacetylation. RNA 15(1):153–175

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  170. Seyedarabi A, Sullivan JA, Sasakawa C, Pickersgill RW (2010) A disulfide driven domain swap switches off the activity of Shigella IpaH9.8 E3 ligase. FEBS Lett 584(19):4163–4168

    Article  CAS  PubMed  Google Scholar 

  171. Song EJ, Werner SL, Neubauer J, Stegmeier F, Aspden J, Rio D, Harper JW, Elledge SJ, Kirschner MW, Rape M (2010) The Prp19 complex and the Usp4Sart3 deubiquitinating enzyme control reversible ubiquitination at the spliceosome. Genes Dev 24(13):1434–1447

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  172. Kaida D, Motoyoshi H, Tashiro E, Nojima T, Hagiwara M, Ishigami K, Watanabe H, Kitahara T, Yoshida T, Nakajima H et al (2007) Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat Chem Biol 3(9):576–583

    Article  CAS  PubMed  Google Scholar 

  173. Habelhah H, Shah K, Huang L, Ostareck-Lederer A, Burlingame AL, Shokat KM, Hentze MW, Ronai Z (2001) ERK phosphorylation drives cytoplasmic accumulation of hnRNP-K and inhibition of mRNA translation. Nat Cell Biol 3(3):325–330

    Article  CAS  PubMed  Google Scholar 

  174. Razanau A, Xie J (2013) Emerging mechanisms and consequences of calcium regulation of alternative splicing in neurons and endocrine cells. Cell Mol Life Sci 70(23):4527–4536

    Article  CAS  PubMed  Google Scholar 

  175. van der Houven van Oordt W, Diaz-Meco MT, Lozano J, Krainer AR, Moscat J, Caceres JF (2000) The MKK(3/6)-p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. J Cell Biol 149(2):307–316

    Article  PubMed Central  PubMed  Google Scholar 

  176. Allemand E, Guil S, Myers M, Moscat J, Caceres JF, Krainer AR (2005) Regulation of heterogenous nuclear ribonucleoprotein A1 transport by phosphorylation in cells stressed by osmotic shock. Proc Natl Acad Sci USA 102(10):3605–3610

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  177. Xie J, Lee JA, Kress TL, Mowry KL, Black DL (2003) Protein kinase A phosphorylation modulates transport of the polypyrimidine tract-binding protein. Proc Natl Acad Sci USA 100(15):8776–8781

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  178. Ma S, Liu G, Sun Y, Xie J (2007) Relocalization of the polypyrimidine tract-binding protein during PKA-induced neurite growth. Biochim Biophys Acta 1773(6):912–923

    Article  CAS  PubMed  Google Scholar 

  179. Caceres JF, Screaton GR, Krainer AR (1998) A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm. Genes Dev 12(1):55–66

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  180. Tacke R, Chen Y, Manley JL (1997) Sequence-specific RNA binding by an SR protein requires RS domain phosphorylation: creation of an SRp40-specific splicing enhancer. Proc Natl Acad Sci USA 94(4):1148–1153

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  181. Cao W, Jamison SF, Garcia-Blanco MA (1997) Both phosphorylation and dephosphorylation of ASF/SF2 are required for pre-mRNA splicing in vitro. RNA 3(12):1456–1467

    PubMed Central  CAS  PubMed  Google Scholar 

  182. Xiao SH, Manley JL (1998) Phosphorylation-dephosphorylation differentially affects activities of splicing factor ASF/SF2. EMBO J 17(21):6359–6367

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  183. Ma CT, Ghosh G, Fu XD, Adams JA (2010) Mechanism of dephosphorylation of the SR protein ASF/SF2 by protein phosphatase 1. J Mol Biol 403(3):386–404

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  184. Dagher SF, Fu XD (2001) Evidence for a role of Sky1p-mediated phosphorylation in 3′ splice site recognition involving both Prp8 and Prp17/Slu4. RNA 7(9):1284–1297

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  185. Prasad J, Colwill K, Pawson T, Manley JL (1999) The protein kinase Clk/Sty directly modulates SR protein activity: both hyper- and hypophosphorylation inhibit splicing. Mol Cell Biol 19(10):6991–7000

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  186. Shin C, Manley JL (2002) The SR protein SRp38 represses splicing in M phase cells. Cell 111(3):407–417

    Article  CAS  PubMed  Google Scholar 

  187. Shin C, Feng Y, Manley JL (2004) Dephosphorylated SRp38 acts as a splicing repressor in response to heat shock. Nature 427(6974):553–558

    Article  CAS  PubMed  Google Scholar 

  188. Boisvert FM, Cote J, Boulanger MC, Richard S (2003) A proteomic analysis of arginine-methylated protein complexes. Mol Cell Proteomics 2(12):1319–1330

    Article  CAS  PubMed  Google Scholar 

  189. Koumbadinga G, Mahmood N, Lei L, Kan YC, Cao WG, Lobo VG, Yao XJ, Zhang SZ, Xie J (2015) Increased stability of heterogeneous ribonucleoproteins by a deacetylase inhibitor. BBA-Gene Regul Mech 1849(8):1095–1103

    Google Scholar 

  190. Okuda J, Toyotome T, Kataoka N, Ohno M, Abe H, Shimura Y, Seyedarabi A, Pickersgill R, Sasakawa C (2005) Shigella effector IpaH9.8 binds to a splicing factor U2AF(35) to modulate host immune responses. Biochem Biophys Res Commun 333(2):531–539

    Article  CAS  PubMed  Google Scholar 

  191. Wahl MC, Will CL, Luhrmann R (2009) The spliceosome: design principles of a dynamic RNP machine. Cell 136(4):701–718

    Article  CAS  PubMed  Google Scholar 

  192. Bellare P, Kutach AK, Rines AK, Guthrie C, Sontheimer EJ (2006) Ubiquitin binding by a variant Jab1/MPN domain in the essential pre-mRNA splicing factor Prp8p. RNA 12(2):292–302

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  193. Bellare P, Small EC, Huang X, Wohlschlegel JA, Staley JP, Sontheimer EJ (2008) A role for ubiquitin in the spliceosome assembly pathway. Nat Struct Mol Biol 15(5):444–451

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  194. Kotake Y, Sagane K, Owa T, Mimori-Kiyosue Y, Shimizu H, Uesugi M, Ishihama Y, Iwata M, Mizui Y (2007) Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat Chem Biol 3(9):570–575

    Article  CAS  PubMed  Google Scholar 

  195. Nakajima H, Sato B, Fujita T, Takase S, Terano H, Okuhara M (1996) New antitumor substances, FR901463, FR901464 and FR901465. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities. J Antibiot (Tokyo) 49(12):1196–1203

    Article  CAS  Google Scholar 

  196. Gozani O, Potashkin J, Reed R (1998) A potential role for U2AF-SAP 155 interactions in recruiting U2 snRNP to the branch site. Mol Cell Biol 18(8):4752–4760

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  197. Konarska MM, Sharp PA (1987) Interactions between small nuclear ribonucleoprotein particles in formation of spliceosomes. Cell 49(6):763–774

    Article  CAS  PubMed  Google Scholar 

  198. Pikielny CW, Rymond BC, Rosbash M (1986) Electrophoresis of ribonucleoproteins reveals an ordered assembly pathway of yeast splicing complexes. Nature 324(6095):341–345

    Article  CAS  PubMed  Google Scholar 

  199. Rutz B, Seraphin B (1999) Transient interaction of BBP/ScSF1 and Mud2 with the splicing machinery affects the kinetics of spliceosome assembly. RNA 5(6):819–831

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  200. Corrionero A, Minana B, Valcarcel J (2011) Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes Dev 25(5):445–459

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  201. Roybal GA, Jurica MS (2010) Spliceostatin A inhibits spliceosome assembly subsequent to prespliceosome formation. Nucleic Acids Res 38(19):6664–6672

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  202. Alekseyenko AV, Kim N, Lee CJ (2007) Global analysis of exon creation versus loss and the role of alternative splicing in 17 vertebrate genomes. RNA 13(5):661–670

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  203. Barbosa-Morais NL, Irimia M, Pan Q, Xiong HY, Gueroussov S, Lee LJ, Slobodeniuc V, Kutter C, Watt S, Colak R et al (2012) The evolutionary landscape of alternative splicing in vertebrate species. Science 338(6114):1587–1593

    Article  CAS  PubMed  Google Scholar 

  204. Merkin J, Russell C, Chen P, Burge CB (2012) Evolutionary dynamics of gene and isoform regulation in Mammalian tissues. Science 338(6114):1593–1599

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  205. Kondrashov FA, Koonin EV (2001) Origin of alternative splicing by tandem exon duplication. Hum Mol Genet 10(23):2661–2669

    Article  CAS  PubMed  Google Scholar 

  206. Krull M, Brosius J, Schmitz J (2005) Alu-SINE exonization: en route to protein-coding function. Mol Biol Evol 22(8):1702–1711

    Article  CAS  PubMed  Google Scholar 

  207. Sorek R (2007) The birth of new exons: mechanisms and evolutionary consequences. RNA 13(10):1603–1608

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  208. Sorek R, Ast G, Graur D (2002) Alu-containing exons are alternatively spliced. Genome Res 12(7):1060–1067

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  209. Keren H, Lev-Maor G, Ast G (2010) Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet 11(5):345–355

    Article  CAS  PubMed  Google Scholar 

  210. Pan Q, Bakowski MA, Morris Q, Zhang W, Frey BJ, Hughes TR, Blencowe BJ (2005) Alternative splicing of conserved exons is frequently species-specific in human and mouse. Trends Genet 21(2):73–77

    Article  CAS  PubMed  Google Scholar 

  211. Lev-Maor G, Goren A, Sela N, Kim E, Keren H, Doron-Faigenboim A, Leibman-Barak S, Pupko T, Ast G (2007) The “alternative” choice of constitutive exons throughout evolution. PLoS Genet 3(11):e203

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  212. Koren E, Lev-Maor G, Ast G (2007) The emergence of alternative 3′ and 5′ splice site exons from constitutive exons. PLoS Comput Biol 3(5):e95

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  213. Yeo G, Hoon S, Venkatesh B, Burge CB (2004) Variation in sequence and organization of splicing regulatory elements in vertebrate genes. Proc Natl Acad Sci USA 101(44):15700–15705

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  214. Xie J (2014) Differential evolution of signal-responsive RNA elements and upstream factors that control alternative splicing. Cell Mol Life Sci 71(22):4347–4360

    Article  CAS  PubMed  Google Scholar 

  215. Sohail M, Xie J (2015) Evolutionary emergence of a novel splice variant of opposite effect on cell cycle. Mol Cell Biol 35(12):2203–2214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Liu G, Lei L, Yu J, Kung S, Xie J (2014) Refinement of the spectra of exon usage by combined effects of extracellular stimulus and intracellular factors. Biochim Biophys Acta 1839(7):537–545

    Article  CAS  PubMed  Google Scholar 

  217. Schor IE, Rascovan N, Pelisch F, Allo M, Kornblihtt AR (2009) Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing. Proc Natl Acad Sci USA 106(11):4325–4330

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  218. Sanchez SE, Petrillo E, Beckwith EJ, Zhang X, Rugnone ML, Hernando CE, Cuevas JC, Godoy Herz MA, Depetris-Chauvin A, Simpson CG et al (2010) A methyl transferase links the circadian clock to the regulation of alternative splicing. Nature 468(7320):112–116

    Article  CAS  PubMed  Google Scholar 

  219. Cech TR, Steitz JA (2014) The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157(1):77–94

    Article  CAS  PubMed  Google Scholar 

  220. Kishore S, Stamm S (2006) The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311(5758):230–232

    Article  CAS  PubMed  Google Scholar 

  221. Beltran M, Puig I, Pena C, Garcia JM, Alvarez AB, Pena R, Bonilla F, de Herreros AG (2008) A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev 22(6):756–769

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  222. Hastings ML, Milcarek C, Martincic K, Peterson ML, Munroe SH (1997) Expression of the thyroid hormone receptor gene, erbAalpha, in B lymphocytes: alternative mRNA processing is independent of differentiation but correlates with antisense RNA levels. Nucleic Acids Res 25(21):4296–4300

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  223. Morrissy AS, Griffith M, Marra MA (2011) Extensive relationship between antisense transcription and alternative splicing in the human genome. Genome Res 21(8):1203–1212

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  224. Yan MD, Hong CC, Lai GM, Cheng AL, Lin YW, Chuang SE (2005) Identification and characterization of a novel gene Saf transcribed from the opposite strand of Fas. Hum Mol Genet 14(11):1465–1474

    Article  CAS  PubMed  Google Scholar 

  225. Kralovicova J, Knut M, Cross NC, Vorechovsky I (2015) Identification of U2AF(35)-dependent exons by RNA-Seq reveals a link between 3′ splice-site organization and activity of U2AF-related proteins. Nucleic Acids Res 43(7):3747–3763

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  226. Saltzman AL, Kim YK, Pan Q, Fagnani MM, Maquat LE, Blencowe BJ (2008) Regulation of multiple core spliceosomal proteins by alternative splicing-coupled nonsense-mediated mRNA decay. Mol Cell Biol 28(13):4320–4330

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  227. Wollerton MC, Gooding C, Robinson F, Brown EC, Jackson RJ, Smith CW (2001) Differential alternative splicing activity of isoforms of polypyrimidine tract binding protein (PTB). RNA 7(6):819–832

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  228. Pink RC, Wicks K, Caley DP, Punch EK, Jacobs L, Carter DR (2011) Pseudogenes: pseudo-functional or key regulators in health and disease? RNA 17(5):792–798

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  229. Yeo GW, Van Nostrand EL, Liang TY (2007) Discovery and analysis of evolutionarily conserved intronic splicing regulatory elements. PLoS Genet 3(5):e85

    Article  PubMed Central  PubMed  Google Scholar 

  230. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M et al (2011) Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478(7367):64–69

    Article  CAS  PubMed  Google Scholar 

  231. Patnaik MM, Lasho TL, Finke CM, Hanson CA, Hodnefield JM, Knudson RA, Ketterling RP, Pardanani A, Tefferi A (2013) Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance. Am J Hematol 88(3):201–206

    Article  CAS  PubMed  Google Scholar 

  232. Cazzola M, Della Porta MG, Malcovati L (2013) The genetic basis of myelodysplasia and its clinical relevance. Blood 122(25):4021–4034

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  233. Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, Yoon CJ, Ellis P, Wedge DC, Pellagatti A et al (2013) Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122(22):3616–3627 (quiz 3699)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work is supported by the Natural Sciences and Engineering Council of Canada (NSERC, #RGPIN/385807-2010), the Canadian Institutes of Health Research (CIHR, FRN_106608) and Research Manitoba.

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Authors and Affiliations

  1. Department of Physiology and Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada

    Muhammad Sohail & Jiuyong Xie

  2. Department of Biochemistry and Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada

    Jiuyong Xie

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  1. Muhammad Sohail
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Correspondence to Jiuyong Xie.

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Sohail, M., Xie, J. Diverse regulation of 3′ splice site usage. Cell. Mol. Life Sci. 72, 4771–4793 (2015). https://doi.org/10.1007/s00018-015-2037-5

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  • DOI: https://doi.org/10.1007/s00018-015-2037-5

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