RNA-Binding Proteins in Regulation of Alternative Cleavage and Polyadenylation

  • Dinghai Zheng
  • Bin TianEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 825)


Almost all eukaryotic pre-mRNAs are processed at the 3′ end by the cleavage and polyadenylation (C/P) reaction, which preludes termination of transcription and gives rise to the poly(A) tail of mature mRNA. Genomic studies in recent years have indicated that most eukaryotic mRNA genes have multiple cleavage and polyadenylation sites (pAs), leading to alternative cleavage and polyadenylation (APA) products. APA isoforms generally differ in their 3′ untranslated regions (3′ UTRs), but can also have different coding sequences (CDSs). APA expands the repertoire of transcripts expressed from the genome, and is highly regulated under various physiological and pathological conditions. Growing lines of evidence have shown that RNA-binding proteins (RBPs) play important roles in regulation of APA. Some RBPs are part of the machinery for C/P; others influence pA choice through binding to adjacent regions. In this chapter, we review cis elements and trans factors involved in C/P, the significance of APA, and increasingly elucidated roles of RBPs in APA regulation. We also discuss analysis of APA using transcriptome-wide techniques as well as molecular biology approaches.


RNA processing Alternative cleavage and polyadenylation 3′ UTR Post-transcriptional regulation Genomics Bioinformatics Deep sequencing 


  1. Abad X, Vera M, Jung SP, Oswald E, Romero I, Amin V, Fortes P, Gunderson SI (2008) Requirements for gene silencing mediated by U1 snRNA binding to a target sequence. Nucleic Acids Res 36:2338–2352PubMedCentralPubMedGoogle Scholar
  2. Alkan SA, Martincic K, Milcarek C (2006) The hnRNPs F and H2 bind to similar sequences to influence gene expression. Biochem J 393:361–371PubMedCentralPubMedGoogle Scholar
  3. Andreassi C, Riccio A (2009) To localize or not to localize: mRNA fate is in 3′ UTR ends. Trends Cell Biol 19:465–474PubMedGoogle Scholar
  4. Bagga PS, Arhin GK, Wilusz J (1998) DSEF-1 is a member of the hnRNP H family of RNA-binding proteins and stimulates pre-mRNA cleavage and polyadenylation in vitro. Nucleic Acids Res 26:5343–5350PubMedCentralPubMedGoogle Scholar
  5. Bai Y, Auperin TC, Chou CY, Chang GG, Manley JL, Tong L (2007) Crystal structure of murine CstF-77: dimeric association and implications for polyadenylation of mRNA precursors. Mol Cell 25:863–875PubMedGoogle Scholar
  6. Barabino SM, Hubner W, Jenny A, Minvielle-Sebastia L, Keller W (1997) The 30-kDa subunit of mammalian cleavage and polyadenylation specificity factor and its yeast homolog are RNA-binding zinc finger proteins. Genes Dev 11:1703–1716PubMedGoogle Scholar
  7. Beaudoing E, Freier S, Wyatt JR, Claverie JM, Gautheret D (2000) Patterns of variant polyadenylation signal usage in human genes. Genome Res 10:1001–1010PubMedCentralPubMedGoogle Scholar
  8. Beaudoing E, Gautheret D (2001) Identification of alternate polyadenylation sites and analysis of their tissue distribution using EST data. Genome Res 11:1520–1526PubMedCentralPubMedGoogle Scholar
  9. Berg MG, Singh LN, Younis I, Liu Q, Pinto AM, Kaida D, Zhang Z, Cho S, Sherrill-Mix S, Wan L et al (2012) U1 snRNP determines mRNA length and regulates isoform expression. Cell 150:53–64PubMedCentralPubMedGoogle Scholar
  10. Blencowe BJ, Issner R, Nickerson JA, Sharp PA (1998) A coactivator of pre-mRNA splicing. Genes Dev 12:996–1009PubMedCentralPubMedGoogle Scholar
  11. Brown KM, Gilmartin GM (2003) A mechanism for the regulation of pre-mRNA 3′ processing by human cleavage factor Im. Mol Cell 12:1467–1476PubMedGoogle Scholar
  12. Campos AR, Grossman D, White K (1985) Mutant alleles at the locus elav in Drosophila melanogaster lead to nervous system defects. A developmental-genetic analysis. J Neurogenet 2:197–218PubMedGoogle Scholar
  13. Castelo-Branco P, Furger A, Wollerton M, Smith C, Moreira A, Proudfoot N (2004) Polypyrimidine tract binding protein modulates efficiency of polyadenylation. Mol Cell Biol 24:4174–4183PubMedCentralPubMedGoogle Scholar
  14. Chan S, Choi EA, Shi Y (2011) Pre-mRNA 3′-end processing complex assembly and function. Wiley Interdiscip Rev RNA 2:321–335PubMedCentralPubMedGoogle Scholar
  15. Chen F, MacDonald CC, Wilusz J (1995) Cleavage site determinants in the mammalian polyadenylation signal. Nucleic Acids Res 23:2614–2620PubMedCentralPubMedGoogle Scholar
  16. Cheng Y, Miura RM, Tian B (2006) Prediction of mRNA polyadenylation sites by support vector machine. Bioinformatics 22:2320–2325PubMedGoogle Scholar
  17. Chkheidze AN, Liebhaber SA (2003) A novel set of nuclear localization signals determine distributions of the alphaCP RNA-binding proteins. Mol Cell Biol 23:8405–8415PubMedCentralPubMedGoogle Scholar
  18. Chkheidze AN, Lyakhov DL, Makeyev AV, Morales J, Kong J, Liebhaber SA (1999) Assembly of the alpha-globin mRNA stability complex reflects binary interaction between the pyrimidine-rich 3′ untranslated region determinant and poly(C) binding protein alphaCP. Mol Cell Biol 19:4572–4581PubMedCentralPubMedGoogle Scholar
  19. Colgan DF, Manley JL (1997) Mechanism and regulation of mRNA polyadenylation. Genes Dev 11:2755–2766PubMedGoogle Scholar
  20. D’Mello V, Lee JY, MacDonald CC, Tian B (2006) Alternative mRNA polyadenylation can potentially affect detection of gene expression by affymetrix genechip arrays. Appl Bioinformatics 5:249–253PubMedGoogle Scholar
  21. Dai W, Zhang G, Makeyev EV (2012) RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage. Nucleic Acids Res 40:787–800PubMedCentralPubMedGoogle Scholar
  22. Danckwardt S, Kaufmann I, Gentzel M, Foerstner KU, Gantzert AS, Gehring NH, Neu-Yilik G, Bork P, Keller W, Wilm M et al (2007) Splicing factors stimulate polyadenylation via USEs at non-canonical 3′ end formation signals. EMBO J 26:2658–2669PubMedCentralPubMedGoogle Scholar
  23. Dantonel JC, Murthy KG, Manley JL, Tora L (1997) Transcription factor TFIID recruits factor CPSF for formation of 3′ end of mRNA. Nature 389:399–402PubMedGoogle Scholar
  24. de Klerk E, Venema A, Anvar SY, Goeman JJ, Hu O, Trollet C, Dickson G, den Dunnen JT, van der Maarel SM, Raz V et al (2012) Poly(A) binding protein nuclear 1 levels affect alternative polyadenylation. Nucleic Acids Res 40:9089–9101PubMedCentralPubMedGoogle Scholar
  25. de Vries H, Ruegsegger U, Hubner W, Friedlein A, Langen H, Keller W (2000) Human pre-mRNA cleavage factor II(m) contains homologs of yeast proteins and bridges two other cleavage factors. EMBO J 19:5895–5904PubMedCentralPubMedGoogle Scholar
  26. Decorsiere A, Cayrel A, Vagner S, Millevoi S (2011) Essential role for the interaction between hnRNP H/F and a G quadruplex in maintaining p53 pre-mRNA 3′-end processing and function during DNA damage. Genes Dev 25:220–225PubMedCentralPubMedGoogle Scholar
  27. Derti A, Garrett-Engele P, Macisaac KD, Stevens RC, Sriram S, Chen R, Rohl CA, Johnson JM, Babak T (2012) A quantitative atlas of polyadenylation in five mammals. Genome Res 22:1173–1183PubMedCentralPubMedGoogle Scholar
  28. Di Giammartino DC, Nishida K, Manley JL (2011) Mechanisms and consequences of alternative polyadenylation. Mol Cell 43:853–866PubMedCentralPubMedGoogle Scholar
  29. Di Giammartino DC, Shi Y, Manley JL (2013) PARP1 represses PAP and inhibits polyadenylation during heat shock. Mol Cell 49:7–17PubMedCentralPubMedGoogle Scholar
  30. Dichtl B, Keller W (2001) Recognition of polyadenylation sites in yeast pre-mRNAs by cleavage and polyadenylation factor. EMBO J 20:3197–3209PubMedCentralPubMedGoogle Scholar
  31. Dittmar KA, Jiang P, Park JW, Amirikian K, Wan J, Shen S, Xing Y, Carstens RP (2012) Genome-wide determination of a broad ESRP-regulated posttranscriptional network by high-throughput sequencing. Mol Cell Biol 32:1468–1482PubMedCentralPubMedGoogle Scholar
  32. Dolken L, Ruzsics Z, Radle B, Friedel CC, Zimmer R, Mages J, Hoffmann R, Dickinson P, Forster T, Ghazal P et al (2008) High-resolution gene expression profiling for simultaneous kinetic parameter analysis of RNA synthesis and decay. RNA 14:1959–1972PubMedCentralPubMedGoogle Scholar
  33. Dreyfuss G, Kim VN, Kataoka N (2002) Messenger-RNA-binding proteins and the messages they carry. Nat Rev Mol Cell Biol 3:195–205PubMedGoogle Scholar
  34. Elkon R, Drost J, van Haaften G, Jenal M, Schrier M, Vrielink JA, Agami R (2012) E2F mediates enhanced alternative polyadenylation in proliferation. Genome Biol 13:R59PubMedCentralPubMedGoogle Scholar
  35. Flavell SW, Kim TK, Gray JM, Harmin DA, Hemberg M, Hong EJ, Markenscoff-Papadimitriou E, Bear DM, Greenberg ME (2008) Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60:1022–1038PubMedCentralPubMedGoogle Scholar
  36. Fortes P, Cuevas Y, Guan F, Liu P, Pentlicky S, Jung SP, Martinez-Chantar ML, Prieto J, Rowe D, Gunderson SI (2003) Inhibiting expression of specific genes in mammalian cells with 5′ end-mutated U1 small nuclear RNAs targeted to terminal exons of pre-mRNA. Proc Natl Acad Sci U S A 100:8264–8269PubMedCentralPubMedGoogle Scholar
  37. Fox-Walsh K, Davis-Turak J, Zhou Y, Li H, Fu XD (2011) A multiplex RNA-seq strategy to profile poly(A+) RNA: application to analysis of transcription response and 3′ end formation. Genomics 98:266–271PubMedCentralPubMedGoogle Scholar
  38. Fu Y, Sun Y, Li Y, Li J, Rao X, Chen C, Xu A (2011) Differential genome-wide profiling of tandem 3′ UTRs among human breast cancer and normal cells by high-throughput sequencing. Genome Res 21:741–747PubMedCentralPubMedGoogle Scholar
  39. Gautheret D, Poirot O, Lopez F, Audic S, Claverie JM (1998) Alternate polyadenylation in human mRNAs: a large-scale analysis by EST clustering. Genome Res 8:524–530PubMedGoogle Scholar
  40. Gilat R, Goncharov S, Esterman N, Shweiki D (2006) Under-representation of PolyA/PolyT tailed ESTs in human ESTdb: an obstacle to alternative polyadenylation inference. Bioinformation 1:220–224PubMedCentralPubMedGoogle Scholar
  41. Glover-Cutter K, Kim S, Espinosa J, Bentley DL (2008) RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes. Nat Struct Mol Biol 15:71–78PubMedCentralPubMedGoogle Scholar
  42. Gruber AR, Martin G, Keller W, Zavolan M (2012) Cleavage factor Im is a key regulator of 3′ UTR length. RNA Biol 9:1405–1412PubMedGoogle Scholar
  43. Gunderson SI, Beyer K, Martin G, Keller W, Boelens WC, Mattaj LW (1994) The human U1A snRNP protein regulates polyadenylation via a direct interaction with poly(A) polymerase. Cell 76:531–541PubMedGoogle Scholar
  44. Gunderson SI, Polycarpou-Schwarz M, Mattaj IW (1998) U1 snRNP inhibits pre-mRNA polyadenylation through a direct interaction between U1 70K and poly(A) polymerase. Mol Cell 1:255–264PubMedGoogle Scholar
  45. Hafner M, Renwick N, Brown M, Mihailovic A, Holoch D, Lin C, Pena JT, Nusbaum JD, Morozov P, Ludwig J et al (2011) RNA-ligase-dependent biases in miRNA representation in deep-sequenced small RNA cDNA libraries. RNA 17:1697–1712PubMedCentralPubMedGoogle Scholar
  46. Hilgers V, Lemke SB, Levine M (2012) ELAV mediates 3′ UTR extension in the Drosophila nervous system. Genes Dev 26:2259–2264PubMedCentralPubMedGoogle Scholar
  47. Hofmann I, Schnolzer M, Kaufmann I, Franke WW (2002) Symplekin, a constitutive protein of karyo- and cytoplasmic particles involved in mRNA biogenesis in Xenopus laevis oocytes. Mol Biol Cell 13:1665–1676PubMedCentralPubMedGoogle Scholar
  48. Hoque M, Ji Z, Zheng D, Luo W, Li W, You B, Park JY, Yehia G, Tian B (2013) Analysis of alternative cleavage and polyadenylation by 3′ region extraction and deep sequencing. Nat Methods 10:133–139PubMedCentralPubMedGoogle Scholar
  49. Hu J, Lutz CS, Wilusz J, Tian B (2005) Bioinformatic identification of candidate cis-regulatory elements involved in human mRNA polyadenylation. RNA 11:1485–1493PubMedCentralPubMedGoogle Scholar
  50. Huang Y, Li W, Yao X, Lin QJ, Yin JW, Liang Y, Heiner M, Tian B, Hui J, Wang G (2012) Mediator complex regulates alternative mRNA processing via the MED23 subunit. Mol Cell 45:459–469PubMedCentralPubMedGoogle Scholar
  51. Hung LH, Heiner M, Hui J, Schreiner S, Benes V, Bindereif A (2008) Diverse roles of hnRNP L in mammalian mRNA processing: a combined microarray and RNAi analysis. RNA 14:284–296PubMedCentralPubMedGoogle Scholar
  52. Jan CH, Friedman RC, Ruby JG, Bartel DP (2011) Formation, regulation and evolution of Caenorhabditis elegans 3′ UTRs. Nature 469:97–101PubMedCentralPubMedGoogle Scholar
  53. Jenal M, Elkon R, Loayza-Puch F, van Haaften G, Kuhn U, Menzies FM, Oude Vrielink JA, Bos AJ, Drost J, Rooijers K et al (2012) The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites. Cell 149:538–553PubMedGoogle Scholar
  54. Ji X, Kong J, Liebhaber SA (2011a) An RNA-protein complex links enhanced nuclear 3′ processing with cytoplasmic mRNA stabilization. EMBO J 30:2622–2633PubMedCentralPubMedGoogle Scholar
  55. Ji X, Wan J, Vishnu M, Xing Y, Liebhaber SA (2013) The poly-C binding proteins, alphaCPs, act as global regulators of alternative polyadenylation. Mol Cell Biol 33(13):2560–2573PubMedCentralPubMedGoogle Scholar
  56. Ji Z, Lee JY, Pan Z, Jiang B, Tian B (2009a) Progressive lengthening of 3′ untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development. Proc Natl Acad Sci U S A 106:7028–7033PubMedCentralPubMedGoogle Scholar
  57. Ji Z, Lee JY, Pan Z, Jiang B, Tian B (2009b) Progressive lengthening of 3′ untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development. Proc Natl Acad Sci U S A 106:7028–7033PubMedCentralPubMedGoogle Scholar
  58. Ji Z, Luo W, Li W, Hoque M, Pan Z, Zhao Y, Tian B (2011b) Transcriptional activity regulates alternative cleavage and polyadenylation. Mol Syst Biol 7:534PubMedCentralPubMedGoogle Scholar
  59. Ji Z, Tian B (2009) Reprogramming of 3′ untranslated regions of mRNAs by alternative polyadenylation in generation of pluripotent stem cells from different cell types. PLoS One 4:e8419PubMedCentralPubMedGoogle Scholar
  60. Kaida D, Berg MG, Younis I, Kasim M, Singh LN, Wan L, Dreyfuss G (2010) U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468:664–668PubMedCentralPubMedGoogle Scholar
  61. Katz Y, Wang ET, Airoldi EM, Burge CB (2010) Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods 7:1009–1015PubMedCentralPubMedGoogle Scholar
  62. Kaufmann I, Martin G, Friedlein A, Langen H, Keller W (2004) Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase. EMBO J 23:616–626PubMedCentralPubMedGoogle Scholar
  63. Kerwitz Y, Kuhn U, Lilie H, Knoth A, Scheuermann T, Friedrich H, Schwarz E, Wahle E (2003) Stimulation of poly(A) polymerase through a direct interaction with the nuclear poly(A) binding protein allosterically regulated by RNA. EMBO J 22:3705–3714PubMedCentralPubMedGoogle Scholar
  64. Kiledjian M, Wang X, Liebhaber SA (1995) Identification of two KH domain proteins in the alpha-globin mRNP stability complex. EMBO J 14:4357–4364PubMedCentralPubMedGoogle Scholar
  65. Koushika SP, Lisbin MJ, White K (1996) ELAV, a Drosophila neuron-specific protein, mediates the generation of an alternatively spliced neural protein isoform. Curr Biol 6:1634–1641PubMedGoogle Scholar
  66. Kozarewa I, Ning Z, Quail MA, Sanders MJ, Berriman M, Turner DJ (2009) Amplification-free Illumina sequencing-library preparation facilitates improved mapping and assembly of (G + C)-biased genomes. Nat Methods 6:291–295PubMedCentralPubMedGoogle Scholar
  67. Kubo T, Wada T, Yamaguchi Y, Shimizu A, Handa H (2006) Knock-down of 25 kDa subunit of cleavage factor Im in Hela cells alters alternative polyadenylation within 3′-UTRs. Nucleic Acids Res 34:6264–6271PubMedCentralPubMedGoogle Scholar
  68. Kuhn U, Gundel M, Knoth A, Kerwitz Y, Rudel S, Wahle E (2009) Poly(A) tail length is controlled by the nuclear poly(A)-binding protein regulating the interaction between poly(A) polymerase and the cleavage and polyadenylation specificity factor. J Biol Chem 284:22803–22814PubMedCentralPubMedGoogle Scholar
  69. Kyburz A, Friedlein A, Langen H, Keller W (2006) Direct interactions between subunits of CPSF and the U2 snRNP contribute to the coupling of pre-mRNA 3′ end processing and splicing. Mol Cell 23:195–205PubMedGoogle Scholar
  70. Laishram RS, Anderson RA (2010) The poly A polymerase Star-PAP controls 3′-end cleavage by promoting CPSF interaction and specificity toward the pre-mRNA. EMBO J 29:4132–4145PubMedCentralPubMedGoogle Scholar
  71. Le Hir H, Gatfield D, Izaurralde E, Moore MJ (2001) The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. EMBO J 20:4987–4997PubMedCentralPubMedGoogle Scholar
  72. Legrand P, Pinaud N, Minvielle-Sebastia L, Fribourg S (2007) The structure of the CstF-77 homodimer provides insights into CstF assembly. Nucleic Acids Res 35:4515–4522PubMedCentralPubMedGoogle Scholar
  73. Li H, Tong S, Li X, Shi H, Ying Z, Gao Y, Ge H, Niu L, Teng M (2011) Structural basis of pre-mRNA recognition by the human cleavage factor Im complex. Cell Res 21:1039–1051PubMedCentralPubMedGoogle Scholar
  74. Li Y, Sun Y, Fu Y, Li M, Huang G, Zhang C, Liang J, Huang S, Shen G, Yuan S et al (2012) Dynamic landscape of tandem 3′ UTRs during zebrafish development. Genome Res 22:1899–1906PubMedCentralPubMedGoogle Scholar
  75. Licatalosi DD, Mele A, Fak JJ, Ule J, Kayikci M, Chi SW, Clark TA, Schweitzer AC, Blume JE, Wang X et al (2008) HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456:464–469PubMedCentralPubMedGoogle Scholar
  76. 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 15:2546–2561PubMedCentralPubMedGoogle Scholar
  77. Liu D, Brockman JM, Dass B, Hutchins LN, Singh P, McCarrey JR, MacDonald CC, Graber JH (2007) Systematic variation in mRNA 3′-processing signals during mouse spermatogenesis. Nucleic Acids Res 35:234–246PubMedCentralPubMedGoogle Scholar
  78. Luo C, Tsementzi D, Kyrpides N, Read T, Konstantinidis KT (2012) Direct comparisons of Illumina vs. Roche 454 sequencing technologies on the same microbial community DNA sample. PLoS One 7:e30087PubMedCentralPubMedGoogle Scholar
  79. Lutz CS, Moreira A (2011) Alternative mRNA polyadenylation in eukaryotes: an effective regulator of gene expression. WIREs RNA 2:23–31PubMedCentralPubMedGoogle Scholar
  80. Mandel CR, Kaneko S, Zhang H, Gebauer D, Vethantham V, Manley JL, Tong L (2006) Polyadenylation factor CPSF-73 is the pre-mRNA 3′-end-processing endonuclease. Nature 444:953–956PubMedGoogle Scholar
  81. Mansfield KD, Keene JD (2012) Neuron-specific ELAV/Hu proteins suppress HuR mRNA during neuronal differentiation by alternative polyadenylation. Nucleic Acids Res 40:2734–2746PubMedCentralPubMedGoogle Scholar
  82. Martin G, Gruber AR, Keller W, Zavolan M (2012) Genome-wide analysis of pre-mRNA 3′ end processing reveals a decisive role of human cleavage factor I in the regulation of 3′ UTR length. Cell Rep 1:753–763PubMedGoogle Scholar
  83. Martincic K, Campbell R, Edwalds-Gilbert G, Souan L, Lotze MT, Milcarek C (1998) Increase in the 64-kDa subunit of the polyadenylation/cleavage stimulatory factor during the G0 to S phase transition. Proc Natl Acad Sci U S A 95:11095–11100PubMedCentralPubMedGoogle Scholar
  84. Marzluff WF, Wagner EJ, Duronio RJ (2008) Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nat Rev Genet 9:843–854PubMedCentralPubMedGoogle Scholar
  85. Mayr C, Bartel DP (2009) Widespread shortening of 3′ UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138:673–684PubMedCentralPubMedGoogle Scholar
  86. McCracken S, Lambermon M, Blencowe BJ (2002) SRm160 splicing coactivator promotes transcript 3′-end cleavage. Mol Cell Biol 22:148–160PubMedCentralPubMedGoogle Scholar
  87. McCracken S, Longman D, Johnstone IL, Caceres JF, Blencowe BJ (2003) An evolutionarily conserved role for SRm160 in 3′-end processing that functions independently of exon junction complex formation. J Biol Chem 278:44153–44160PubMedGoogle Scholar
  88. Millevoi S, Decorsiere A, Loulergue C, Iacovoni J, Bernat S, Antoniou M, Vagner S (2009) A physical and functional link between splicing factors promotes pre-mRNA 3′ end processing. Nucleic Acids Res 37:4672–4683PubMedCentralPubMedGoogle Scholar
  89. Millevoi S, Loulergue C, Dettwiler S, Karaa SZ, Keller W, Antoniou M, Vagner S (2006) An interaction between U2AF 65 and CF I(m) links the splicing and 3′ end processing machineries. EMBO J 25:4854–4864PubMedCentralPubMedGoogle Scholar
  90. Miura P, Shenker S, Andreu-Agullo C, Westholm JO, Lai EC (2013) Widespread and extensive lengthening of 3′ UTRs in the mammalian brain. Genome Res 23(5):812–825PubMedCentralPubMedGoogle Scholar
  91. Monarez RR, MacDonald CC, Dass B (2007) Polyadenylation proteins CstF-64 and tauCstF-64 exhibit differential binding affinities for RNA polymers. Biochem J 401:651–658PubMedCentralPubMedGoogle Scholar
  92. Moreira A, Takagaki Y, Brackenridge S, Wollerton M, Manley JL, Proudfoot NJ (1998) The upstream sequence element of the C2 complement poly(A) signal activates mRNA 3′ end formation by two distinct mechanisms. Genes Dev 12:2522–2534PubMedCentralPubMedGoogle Scholar
  93. Moreno-Morcillo M, Minvielle-Sebastia L, Mackereth C, Fribourg S (2011) Hexameric architecture of CstF supported by CstF-50 homodimerization domain structure. RNA 17:412–418PubMedCentralPubMedGoogle Scholar
  94. Morris AR, Bos A, Diosdado B, Rooijers K, Elkon R, Bolijn AS, Carvalho B, Meijer GA, Agami R (2012) Alternative cleavage and polyadenylation during colorectal cancer development. Clin Cancer Res 18:5256–5266PubMedGoogle Scholar
  95. Murthy KG, Manley JL (1995) The 160-kD subunit of human cleavage-polyadenylation specificity factor coordinates pre-mRNA 3′-end formation. Genes Dev 9:2672–2683PubMedGoogle Scholar
  96. Nag A, Narsinh K, Martinson HG (2007) The poly(A)-dependent transcriptional pause is mediated by CPSF acting on the body of the polymerase. Nat Struct Mol Biol 14:662–669PubMedGoogle Scholar
  97. Nagaike T, Logan C, Hotta I, Rozenblatt-Rosen O, Meyerson M, Manley JL (2011) Transcriptional activators enhance polyadenylation of mRNA precursors. Mol Cell 41:409–418PubMedCentralPubMedGoogle Scholar
  98. Naganuma T, Nakagawa S, Tanigawa A, Sasaki YF, Goshima N, Hirose T (2012) Alternative 3′-end processing of long noncoding RNA initiates construction of nuclear paraspeckles. EMBO J 31:4020–4034PubMedCentralPubMedGoogle Scholar
  99. Nam DK, Lee S, Zhou G, Cao X, Wang C, Clark T, Chen J, Rowley JD, Wang SM (2002) Oligo(dT) primer generates a high frequency of truncated cDNAs through internal poly(A) priming during reverse transcription. Proc Natl Acad Sci U S A 99:6152–6156PubMedCentralPubMedGoogle Scholar
  100. Newman CS, Krieg PA (1999) Ribonuclease protection analysis of gene expression in Xenopus. Methods Mol Biol 127:29–40PubMedGoogle Scholar
  101. Nunes NM, Li W, Tian B, Furger A (2010) A functional human Poly(A) site requires only a potent DSE and an A-rich upstream sequence. EMBO J 29:1523–1536PubMedCentralPubMedGoogle Scholar
  102. Okubo K, Hori N, Matoba R, Niiyama T, Fukushima A, Kojima Y, Matsubara K (1992) Large scale cDNA sequencing for analysis of quantitative and qualitative aspects of gene expression. Nat Genet 2:173–179PubMedGoogle Scholar
  103. Ozsolak F, Kapranov P, Foissac S, Kim SW, Fishilevich E, Monaghan AP, John B, Milos PM (2010) Comprehensive polyadenylation site maps in yeast and human reveal pervasive alternative polyadenylation. Cell 143:1018–1029PubMedCentralPubMedGoogle Scholar
  104. Ozsolak F, Milos PM (2011) Transcriptome profiling using single-molecule direct RNA sequencing. Methods Mol Biol 733:51–61PubMedCentralPubMedGoogle Scholar
  105. Ozsolak F, Platt AR, Jones DR, Reifenberger JG, Sass LE, McInerney P, Thompson JF, Bowers J, Jarosz M, Milos PM (2009) Direct RNA sequencing. Nature 461:814–818PubMedGoogle Scholar
  106. Pan Z, Zhang H, Hague LK, Lee JY, Lutz CS, Tian B (2006) An intronic polyadenylation site in human and mouse CstF-77 genes suggests an evolutionarily conserved regulatory mechanism. Gene 366:325–334PubMedGoogle Scholar
  107. Pauws E, van Kampen AH, van de Graaf SA, de Vijlder JJ, Ris-Stalpers C (2001) Heterogeneity in polyadenylation cleavage sites in mammalian mRNA sequences: implications for SAGE analysis. Nucleic Acids Res 29:1690–1694PubMedCentralPubMedGoogle Scholar
  108. Perez Canadillas JM, Varani G (2003) Recognition of GU-rich polyadenylation regulatory elements by human CstF-64 protein. EMBO J 22:2821–2830PubMedCentralPubMedGoogle Scholar
  109. Phillips C, Pachikara N, Gunderson SI (2004) U1A inhibits cleavage at the immunoglobulin M heavy-chain secretory poly(A) site by binding between the two downstream GU-rich regions. Mol Cell Biol 24:6162–6171PubMedCentralPubMedGoogle Scholar
  110. Prasanth KV, Prasanth SG, Xuan Z, Hearn S, Freier SM, Bennett CF, Zhang MQ, Spector DL (2005) Regulating gene expression through RNA nuclear retention. Cell 123:249–263PubMedGoogle Scholar
  111. Proudfoot NJ, Brownlee GG (1976) 3′ non-coding region sequences in eukaryotic messenger RNA. Nature 263:211–214PubMedGoogle Scholar
  112. Quail MA, Smith M, Coupland P, Otto TD, Harris SR, Connor TR, Bertoni A, Swerdlow HP, Gu Y (2012) A tale of three next generation sequencing platforms: comparison of Ion Torrent, Pacific Biosciences and Illumina MiSeq sequencers. BMC Genomics 13:341PubMedCentralPubMedGoogle Scholar
  113. Roca X, Karginov FV (2012) RNA biology in a test tube—an overview of in vitro systems/assays. Wiley Interdiscip Rev RNA 3:509–527PubMedGoogle Scholar
  114. Ruegsegger U, Beyer K, Keller W (1996) Purification and characterization of human cleavage factor Im involved in the 3′ end processing of messenger RNA precursors. J Biol Chem 271:6107–6113PubMedGoogle Scholar
  115. Ryan K, Bauer DL (2008) Finishing touches: post-translational modification of protein factors involved in mammalian pre-mRNA 3′ end formation. Int J Biochem Cell Biol 40:2384–2396PubMedCentralPubMedGoogle Scholar
  116. Sandberg R, Neilson JR, Sarma A, Sharp PA, Burge CB (2008) Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 320:1643–1647PubMedCentralPubMedGoogle Scholar
  117. Sartini BL, Wang H, Wang W, Millette CF, Kilpatrick DL (2008) Pre-messenger RNA cleavage factor I (CFIm): potential role in alternative polyadenylation during spermatogenesis. Biol Reprod 78:472–482PubMedGoogle Scholar
  118. Scotto-Lavino E, Du G, Frohman MA (2006) 3′ end cDNA amplification using classic RACE. Nat Protoc 1:2742–2745PubMedGoogle Scholar
  119. Shepard PJ, Choi EA, Lu J, Flanagan LA, Hertel KJ, Shi Y (2011) Complex and dynamic landscape of RNA polyadenylation revealed by PAS-Seq. RNA 17:761–772PubMedCentralPubMedGoogle Scholar
  120. Sherstnev A, Duc C, Cole C, Zacharaki V, Hornyik C, Ozsolak F, Milos PM, Barton GJ, Simpson GG (2012) Direct sequencing of Arabidopsis thaliana RNA reveals patterns of cleavage and polyadenylation. Nat Struct Mol Biol 19:845–852PubMedCentralPubMedGoogle Scholar
  121. Shi Y, Di Giammartino DC, Taylor D, Sarkeshik A, Rice WJ, Yates JR 3rd, Frank J, Manley JL (2009) Molecular architecture of the human pre-mRNA 3′ processing complex. Mol Cell 33:365–376PubMedCentralPubMedGoogle Scholar
  122. Siegel TN, Hekstra DR, Wang X, Dewell S, Cross GA (2010) Genome-wide analysis of mRNA abundance in two life-cycle stages of Trypanosoma brucei and identification of splicing and polyadenylation sites. Nucleic Acids Res 38:4946–4957PubMedCentralPubMedGoogle Scholar
  123. Singh P, Alley TL, Wright SM, Kamdar S, Schott W, Wilpan RY, Mills KD, Graber JH (2009) Global changes in processing of mRNA 3′ untranslated regions characterize clinically distinct cancer subtypes. Cancer Res 69:9422–9430PubMedCentralPubMedGoogle Scholar
  124. Smibert P, Miura P, Westholm JO, Shenker S, May G, Duff MO, Zhang D, Eads BD, Carlson J, Brown JB et al (2012) Global patterns of tissue-specific alternative polyadenylation in Drosophila. Cell Rep 1:277–289PubMedCentralPubMedGoogle Scholar
  125. Soller M, White K (2003) ELAV inhibits 3′-end processing to promote neural splicing of ewg pre-mRNA. Genes Dev 17:2526–2538PubMedCentralPubMedGoogle Scholar
  126. Soller M, White K (2005) ELAV multimerizes on conserved AU4-6 motifs important for ewg splicing regulation. Mol Cell Biol 25:7580–7591PubMedCentralPubMedGoogle Scholar
  127. Sorefan K, Pais H, Hall AE, Kozomara A, Griffiths-Jones S, Moulton V, Dalmay T (2012) Reducing ligation bias of small RNAs in libraries for next generation sequencing. Silence 3:4PubMedCentralPubMedGoogle Scholar
  128. Takagaki Y, Manley JL (2000) Complex protein interactions within the human polyadenylation machinery identify a novel component. Mol Cell Biol 20:1515–1525PubMedCentralPubMedGoogle Scholar
  129. Takagaki Y, Seipelt RL, Peterson ML, Manley JL (1996) The polyadenylation factor CstF-64 regulates alternative processing of IgM heavy chain pre-mRNA during B cell differentiation. Cell 87:941–952PubMedGoogle Scholar
  130. Tian B, Graber JH (2012) Signals for pre-mRNA cleavage and polyadenylation. Wiley Interdiscip Rev RNA 3:385–396PubMedGoogle Scholar
  131. Tian B, Hu J, Zhang H, Lutz CS (2005) A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Res 33:201–212PubMedCentralPubMedGoogle Scholar
  132. Tian B, Manley JL (2013) Alternative cleavage and polyadenylation: the long and short of it. Trends Biochem Sci 38:312–320PubMedCentralPubMedGoogle Scholar
  133. Tian B, Pan Z, Lee JY (2007) Widespread mRNA polyadenylation events in introns indicate dynamic interplay between polyadenylation and splicing. Genome Res 17:156–165PubMedCentralPubMedGoogle Scholar
  134. Ule J, Stefani G, Mele A, Ruggiu M, Wang X, Taneri B, Gaasterland T, Blencowe BJ, Darnell RB (2006) An RNA map predicting Nova-dependent splicing regulation. Nature 444:580–586PubMedGoogle Scholar
  135. Ulitsky I, Shkumatava A, Jan CH, Subtelny AO, Koppstein D, Bell GW, Sive H, Bartel DP (2012) Extensive alternative polyadenylation during zebrafish development. Genome Res 22:2054–2066PubMedCentralPubMedGoogle Scholar
  136. Velculescu VE, Zhang L, Vogelstein B, Kinzler KW (1995) Serial analysis of gene expression. Science 270:484–487PubMedGoogle Scholar
  137. Venkataraman K, Brown KM, Gilmartin GM (2005) Analysis of a noncanonical poly(A) site reveals a tripartite mechanism for vertebrate poly(A) site recognition. Genes Dev 19:1315–1327PubMedCentralPubMedGoogle Scholar
  138. Veraldi KL, Arhin GK, Martincic K, Chung-Ganster LH, Wilusz J, Milcarek C (2001) hnRNP F influences binding of a 64-kilodalton subunit of cleavage stimulation factor to mRNA precursors in mouse B cells. Mol Cell Biol 21:1228–1238PubMedCentralPubMedGoogle Scholar
  139. 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 456:470–476PubMedCentralPubMedGoogle Scholar
  140. Warzecha CC, Jiang P, Amirikian K, Dittmar KA, Lu H, Shen S, Guo W, Xing Y, Carstens RP (2010) An ESRP-regulated splicing programme is abrogated during the epithelial-mesenchymal transition. EMBO J 29:3286–3300PubMedCentralPubMedGoogle Scholar
  141. Warzecha CC, Shen S, Xing Y, Carstens RP (2009) The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate diverse types of alternative splicing events. RNA Biol 6:546–562PubMedCentralPubMedGoogle Scholar
  142. Weiss IM, Liebhaber SA (1995) Erythroid cell-specific mRNA stability elements in the alpha 2-globin 3′ nontranslated region. Mol Cell Biol 15:2457–2465PubMedCentralPubMedGoogle Scholar
  143. West S, Proudfoot NJ (2008) Human Pcf11 enhances degradation of RNA polymerase II-associated nascent RNA and transcriptional termination. Nucleic Acids Res 36:905–914PubMedCentralPubMedGoogle Scholar
  144. Wilhelm BT, Marguerat S, Watt S, Schubert F, Wood V, Goodhead I, Penkett CJ, Rogers J, Bahler J (2008) Dynamic repertoire of a eukaryotic transcriptome surveyed at single-nucleotide resolution. Nature 453:1239–1243PubMedGoogle Scholar
  145. Windhager L, Bonfert T, Burger K, Ruzsics Z, Krebs S, Kaufmann S, Malterer G, L'Hernault A, Schilhabel M, Schreiber S et al (2012) Ultrashort and progressive 4sU-tagging reveals key characteristics of RNA processing at nucleotide resolution. Genome Res 22:2031–2042PubMedCentralPubMedGoogle Scholar
  146. Wu X, Liu M, Downie B, Liang C, Ji G, Li QQ, Hunt AG (2011) Genome-wide landscape of polyadenylation in Arabidopsis provides evidence for extensive alternative polyadenylation. Proc Natl Acad Sci U S A 108:12533–12538PubMedCentralPubMedGoogle Scholar
  147. 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 36:996–1006PubMedCentralPubMedGoogle Scholar
  148. Yan J, Marr TG (2005) Computational analysis of 3′-ends of ESTs shows four classes of alternative polyadenylation in human, mouse, and rat. Genome Res 15:369–375PubMedCentralPubMedGoogle Scholar
  149. Yang Q, Coseno M, Gilmartin GM, Doublie S (2011) Crystal structure of a human cleavage factor CFI(m)25/CFI(m)68/RNA complex provides an insight into poly(A) site recognition and RNA looping. Structure 19:368–377PubMedCentralPubMedGoogle Scholar
  150. Yang Q, Gilmartin GM, Doublie S (2010) Structural basis of UGUA recognition by the Nudix protein CFI(m)25 and implications for a regulatory role in mRNA 3′ processing. Proc Natl Acad Sci U S A 107:10062–10067PubMedCentralPubMedGoogle Scholar
  151. Yano M, Hayakawa-Yano Y, Mele A, Darnell RB (2010) Nova2 regulates neuronal migration through an RNA switch in disabled-1 signaling. Neuron 66:848–858PubMedCentralPubMedGoogle Scholar
  152. Yao C, Biesinger J, Wan J, Weng L, Xing Y, Xie X, Shi Y (2012) Transcriptome-wide analyses of CstF64-RNA interactions in global regulation of mRNA alternative polyadenylation. Proc Natl Acad Sci U S A 109:18773–18778PubMedCentralPubMedGoogle Scholar
  153. Zhang H, Lee JY, Tian B (2005) Biased alternative polyadenylation in human tissues. Genome Biol 6:R100PubMedCentralPubMedGoogle Scholar
  154. Zhu H, Zhou HL, Hasman RA, Lou H (2007) Hu proteins regulate polyadenylation by blocking sites containing U-rich sequences. J Biol Chem 282:2203–2210PubMedGoogle Scholar
  155. Zhuang F, Fuchs RT, Sun Z, Zheng Y, Robb GB (2012) Structural bias in T4 RNA ligase-mediated 3′-adapter ligation. Nucleic Acids Res 40:e54PubMedCentralPubMedGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyUniversity of Medicine and Dentistry of New Jersey (UMDNJ)-New Jersey Medical SchoolNewarkUSA

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