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RNA-Binding Proteins in Regulation of Alternative Cleavage and Polyadenylation

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Systems Biology of RNA Binding Proteins

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 825))

Abstract

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.

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References

  • 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 36:2338–2352

    CAS  PubMed Central  PubMed  Google Scholar 

  • Alkan SA, Martincic K, Milcarek C (2006) The hnRNPs F and H2 bind to similar sequences to influence gene expression. Biochem J 393:361–371

    CAS  PubMed Central  PubMed  Google Scholar 

  • Andreassi C, Riccio A (2009) To localize or not to localize: mRNA fate is in 3′ UTR ends. Trends Cell Biol 19:465–474

    CAS  PubMed  Google Scholar 

  • 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 26:5343–5350

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 25:863–875

    CAS  PubMed  Google Scholar 

  • 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 11:1703–1716

    CAS  PubMed  Google Scholar 

  • Beaudoing E, Freier S, Wyatt JR, Claverie JM, Gautheret D (2000) Patterns of variant polyadenylation signal usage in human genes. Genome Res 10:1001–1010

    CAS  PubMed Central  PubMed  Google Scholar 

  • Beaudoing E, Gautheret D (2001) Identification of alternate polyadenylation sites and analysis of their tissue distribution using EST data. Genome Res 11:1520–1526

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 150:53–64

    CAS  PubMed Central  PubMed  Google Scholar 

  • Blencowe BJ, Issner R, Nickerson JA, Sharp PA (1998) A coactivator of pre-mRNA splicing. Genes Dev 12:996–1009

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brown KM, Gilmartin GM (2003) A mechanism for the regulation of pre-mRNA 3′ processing by human cleavage factor Im. Mol Cell 12:1467–1476

    CAS  PubMed  Google Scholar 

  • 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 2:197–218

    CAS  PubMed  Google Scholar 

  • 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 24:4174–4183

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chan S, Choi EA, Shi Y (2011) Pre-mRNA 3′-end processing complex assembly and function. Wiley Interdiscip Rev RNA 2:321–335

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen F, MacDonald CC, Wilusz J (1995) Cleavage site determinants in the mammalian polyadenylation signal. Nucleic Acids Res 23:2614–2620

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cheng Y, Miura RM, Tian B (2006) Prediction of mRNA polyadenylation sites by support vector machine. Bioinformatics 22:2320–2325

    CAS  PubMed  Google Scholar 

  • Chkheidze AN, Liebhaber SA (2003) A novel set of nuclear localization signals determine distributions of the alphaCP RNA-binding proteins. Mol Cell Biol 23:8405–8415

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 19:4572–4581

    CAS  PubMed Central  PubMed  Google Scholar 

  • Colgan DF, Manley JL (1997) Mechanism and regulation of mRNA polyadenylation. Genes Dev 11:2755–2766

    CAS  PubMed  Google Scholar 

  • 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 5:249–253

    PubMed  Google Scholar 

  • Dai W, Zhang G, Makeyev EV (2012) RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage. Nucleic Acids Res 40:787–800

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 26:2658–2669

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dantonel JC, Murthy KG, Manley JL, Tora L (1997) Transcription factor TFIID recruits factor CPSF for formation of 3′ end of mRNA. Nature 389:399–402

    CAS  PubMed  Google Scholar 

  • 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 40:9089–9101

    PubMed Central  PubMed  Google Scholar 

  • 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 19:5895–5904

    PubMed Central  PubMed  Google Scholar 

  • 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 25:220–225

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 22:1173–1183

    CAS  PubMed Central  PubMed  Google Scholar 

  • Di Giammartino DC, Nishida K, Manley JL (2011) Mechanisms and consequences of alternative polyadenylation. Mol Cell 43:853–866

    PubMed Central  PubMed  Google Scholar 

  • Di Giammartino DC, Shi Y, Manley JL (2013) PARP1 represses PAP and inhibits polyadenylation during heat shock. Mol Cell 49:7–17

    PubMed Central  PubMed  Google Scholar 

  • Dichtl B, Keller W (2001) Recognition of polyadenylation sites in yeast pre-mRNAs by cleavage and polyadenylation factor. EMBO J 20:3197–3209

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 32:1468–1482

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 14:1959–1972

    PubMed Central  PubMed  Google Scholar 

  • Dreyfuss G, Kim VN, Kataoka N (2002) Messenger-RNA-binding proteins and the messages they carry. Nat Rev Mol Cell Biol 3:195–205

    CAS  PubMed  Google Scholar 

  • 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:R59

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 60:1022–1038

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 100:8264–8269

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 98:266–271

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 21:741–747

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 8:524–530

    CAS  PubMed  Google Scholar 

  • 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 1:220–224

    PubMed Central  PubMed  Google Scholar 

  • 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 15:71–78

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gruber AR, Martin G, Keller W, Zavolan M (2012) Cleavage factor Im is a key regulator of 3′ UTR length. RNA Biol 9:1405–1412

    CAS  PubMed  Google Scholar 

  • 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 76:531–541

    CAS  PubMed  Google Scholar 

  • 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 1:255–264

    CAS  PubMed  Google Scholar 

  • 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 17:1697–1712

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hilgers V, Lemke SB, Levine M (2012) ELAV mediates 3′ UTR extension in the Drosophila nervous system. Genes Dev 26:2259–2264

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 13:1665–1676

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 10:133–139

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hu J, Lutz CS, Wilusz J, Tian B (2005) Bioinformatic identification of candidate cis-regulatory elements involved in human mRNA polyadenylation. RNA 11:1485–1493

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 45:459–469

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 14:284–296

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jan CH, Friedman RC, Ruby JG, Bartel DP (2011) Formation, regulation and evolution of Caenorhabditis elegans 3′ UTRs. Nature 469:97–101

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 149:538–553

    CAS  PubMed  Google Scholar 

  • Ji X, Kong J, Liebhaber SA (2011a) An RNA-protein complex links enhanced nuclear 3′ processing with cytoplasmic mRNA stabilization. EMBO J 30:2622–2633

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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):2560–2573

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 106:7028–7033

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 106:7028–7033

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 7:534

    PubMed Central  PubMed  Google Scholar 

  • 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:e8419

    PubMed Central  PubMed  Google Scholar 

  • 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 468:664–668

    CAS  PubMed Central  PubMed  Google Scholar 

  • Katz Y, Wang ET, Airoldi EM, Burge CB (2010) Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods 7:1009–1015

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 23:616–626

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 22:3705–3714

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kiledjian M, Wang X, Liebhaber SA (1995) Identification of two KH domain proteins in the alpha-globin mRNP stability complex. EMBO J 14:4357–4364

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 6:1634–1641

    CAS  PubMed  Google Scholar 

  • 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 6:291–295

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 34:6264–6271

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 284:22803–22814

    PubMed Central  PubMed  Google Scholar 

  • 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 23:195–205

    CAS  PubMed  Google Scholar 

  • 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 29:4132–4145

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 20:4987–4997

    PubMed Central  PubMed  Google Scholar 

  • 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 35:4515–4522

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 21:1039–1051

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 22:1899–1906

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 456:464–469

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 15:2546–2561

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 35:234–246

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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:e30087

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lutz CS, Moreira A (2011) Alternative mRNA polyadenylation in eukaryotes: an effective regulator of gene expression. WIREs RNA 2:23–31

    PubMed Central  PubMed  Google Scholar 

  • 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 444:953–956

    CAS  PubMed  Google Scholar 

  • Mansfield KD, Keene JD (2012) Neuron-specific ELAV/Hu proteins suppress HuR mRNA during neuronal differentiation by alternative polyadenylation. Nucleic Acids Res 40:2734–2746

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 1:753–763

    CAS  PubMed  Google Scholar 

  • 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 95:11095–11100

    CAS  PubMed Central  PubMed  Google Scholar 

  • Marzluff WF, Wagner EJ, Duronio RJ (2008) Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nat Rev Genet 9:843–854

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mayr C, Bartel DP (2009) Widespread shortening of 3′ UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138:673–684

    CAS  PubMed Central  PubMed  Google Scholar 

  • McCracken S, Lambermon M, Blencowe BJ (2002) SRm160 splicing coactivator promotes transcript 3′-end cleavage. Mol Cell Biol 22:148–160

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 278:44153–44160

    CAS  PubMed  Google Scholar 

  • 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 37:4672–4683

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 25:4854–4864

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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):812–825

    CAS  PubMed Central  PubMed  Google Scholar 

  • Monarez RR, MacDonald CC, Dass B (2007) Polyadenylation proteins CstF-64 and tauCstF-64 exhibit differential binding affinities for RNA polymers. Biochem J 401:651–658

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 12:2522–2534

    CAS  PubMed Central  PubMed  Google Scholar 

  • Moreno-Morcillo M, Minvielle-Sebastia L, Mackereth C, Fribourg S (2011) Hexameric architecture of CstF supported by CstF-50 homodimerization domain structure. RNA 17:412–418

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 18:5256–5266

    CAS  PubMed  Google Scholar 

  • Murthy KG, Manley JL (1995) The 160-kD subunit of human cleavage-polyadenylation specificity factor coordinates pre-mRNA 3′-end formation. Genes Dev 9:2672–2683

    CAS  PubMed  Google Scholar 

  • 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 14:662–669

    CAS  PubMed  Google Scholar 

  • Nagaike T, Logan C, Hotta I, Rozenblatt-Rosen O, Meyerson M, Manley JL (2011) Transcriptional activators enhance polyadenylation of mRNA precursors. Mol Cell 41:409–418

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 31:4020–4034

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 99:6152–6156

    CAS  PubMed Central  PubMed  Google Scholar 

  • Newman CS, Krieg PA (1999) Ribonuclease protection analysis of gene expression in Xenopus. Methods Mol Biol 127:29–40

    CAS  PubMed  Google Scholar 

  • 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 29:1523–1536

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 2:173–179

    CAS  PubMed  Google Scholar 

  • 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 143:1018–1029

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ozsolak F, Milos PM (2011) Transcriptome profiling using single-molecule direct RNA sequencing. Methods Mol Biol 733:51–61

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 461:814–818

    CAS  PubMed  Google Scholar 

  • 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 366:325–334

    CAS  PubMed  Google Scholar 

  • 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 29:1690–1694

    CAS  PubMed Central  PubMed  Google Scholar 

  • Perez Canadillas JM, Varani G (2003) Recognition of GU-rich polyadenylation regulatory elements by human CstF-64 protein. EMBO J 22:2821–2830

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 24:6162–6171

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 123:249–263

    CAS  PubMed  Google Scholar 

  • Proudfoot NJ, Brownlee GG (1976) 3′ non-coding region sequences in eukaryotic messenger RNA. Nature 263:211–214

    CAS  PubMed  Google Scholar 

  • 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 13:341

    CAS  PubMed Central  PubMed  Google Scholar 

  • Roca X, Karginov FV (2012) RNA biology in a test tube—an overview of in vitro systems/assays. Wiley Interdiscip Rev RNA 3:509–527

    CAS  PubMed  Google Scholar 

  • 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 271:6107–6113

    CAS  PubMed  Google Scholar 

  • 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 40:2384–2396

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 320:1643–1647

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 78:472–482

    CAS  PubMed  Google Scholar 

  • Scotto-Lavino E, Du G, Frohman MA (2006) 3′ end cDNA amplification using classic RACE. Nat Protoc 1:2742–2745

    CAS  PubMed  Google Scholar 

  • 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 17:761–772

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 19:845–852

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 33:365–376

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 38:4946–4957

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 69:9422–9430

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 1:277–289

    CAS  PubMed Central  PubMed  Google Scholar 

  • Soller M, White K (2003) ELAV inhibits 3′-end processing to promote neural splicing of ewg pre-mRNA. Genes Dev 17:2526–2538

    CAS  PubMed Central  PubMed  Google Scholar 

  • Soller M, White K (2005) ELAV multimerizes on conserved AU4-6 motifs important for ewg splicing regulation. Mol Cell Biol 25:7580–7591

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 3:4

    CAS  PubMed Central  PubMed  Google Scholar 

  • Takagaki Y, Manley JL (2000) Complex protein interactions within the human polyadenylation machinery identify a novel component. Mol Cell Biol 20:1515–1525

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 87:941–952

    CAS  PubMed  Google Scholar 

  • Tian B, Graber JH (2012) Signals for pre-mRNA cleavage and polyadenylation. Wiley Interdiscip Rev RNA 3:385–396

    CAS  PubMed  Google Scholar 

  • Tian B, Hu J, Zhang H, Lutz CS (2005) A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Res 33:201–212

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tian B, Manley JL (2013) Alternative cleavage and polyadenylation: the long and short of it. Trends Biochem Sci 38:312–320

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tian B, Pan Z, Lee JY (2007) Widespread mRNA polyadenylation events in introns indicate dynamic interplay between polyadenylation and splicing. Genome Res 17:156–165

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 444:580–586

    CAS  PubMed  Google Scholar 

  • 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 22:2054–2066

    CAS  PubMed Central  PubMed  Google Scholar 

  • Velculescu VE, Zhang L, Vogelstein B, Kinzler KW (1995) Serial analysis of gene expression. Science 270:484–487

    CAS  PubMed  Google Scholar 

  • 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 19:1315–1327

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 21:1228–1238

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 456:470–476

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 29:3286–3300

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 6:546–562

    CAS  PubMed Central  PubMed  Google Scholar 

  • Weiss IM, Liebhaber SA (1995) Erythroid cell-specific mRNA stability elements in the alpha 2-globin 3′ nontranslated region. Mol Cell Biol 15:2457–2465

    CAS  PubMed Central  PubMed  Google Scholar 

  • West S, Proudfoot NJ (2008) Human Pcf11 enhances degradation of RNA polymerase II-associated nascent RNA and transcriptional termination. Nucleic Acids Res 36:905–914

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 453:1239–1243

    CAS  PubMed  Google Scholar 

  • 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 22:2031–2042

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 108:12533–12538

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 36:996–1006

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 15:369–375

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 19:368–377

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 107:10062–10067

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yano M, Hayakawa-Yano Y, Mele A, Darnell RB (2010) Nova2 regulates neuronal migration through an RNA switch in disabled-1 signaling. Neuron 66:848–858

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 109:18773–18778

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang H, Lee JY, Tian B (2005) Biased alternative polyadenylation in human tissues. Genome Biol 6:R100

    PubMed Central  PubMed  Google Scholar 

  • Zhu H, Zhou HL, Hasman RA, Lou H (2007) Hu proteins regulate polyadenylation by blocking sites containing U-rich sequences. J Biol Chem 282:2203–2210

    CAS  PubMed  Google Scholar 

  • 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:e54

    CAS  PubMed Central  PubMed  Google Scholar 

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  1. Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey (UMDNJ)-New Jersey Medical School, 185 South Orange Ave., Newark, NJ, 07103, USA

    Dinghai Zheng & Bin Tian

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  1. Dinghai Zheng
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  2. Bin Tian
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  1. UCSD Moores Cancer Center, Institute for Genomic Medicine UCSD Stem Cell Program, La Jolla, California, USA

    Gene W. Yeo

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Zheng, D., Tian, B. (2014). RNA-Binding Proteins in Regulation of Alternative Cleavage and Polyadenylation. In: Yeo, G. (eds) Systems Biology of RNA Binding Proteins. Advances in Experimental Medicine and Biology, vol 825. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1221-6_3

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