Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Alternative cleavage and polyadenylation: extent, regulation and function

Key Points

  • Recent advances in technologies for global mapping of alternative polyadenylation (APA) have allowed unprecedented investigation of alternative polyadenylation in biological processes.

  • Broad APA modulation has been identified in development and cellular differentiation: in general in systems characterized thus far, development is accompanied by a progressive lengthening of 3′ untranslated regions (UTRs) and use of distal poly(A) sites.

  • Cellular proliferation is associated with a use of shift towards proximal poly(A) sites.

  • APA may be regulated by the level of 3′ end machinery expression, interplay with transcription, splicing and potentially chromatin.

  • APA misregulation has been identified in human disease, and APA is potentially a therapeutic target.

Abstract

The 3′ end of most protein-coding genes and long non-coding RNAs is cleaved and polyadenylated. Recent discoveries have revealed that a large proportion of these genes contains more than one polyadenylation site. Therefore, alternative polyadenylation (APA) is a widespread phenomenon, generating mRNAs with alternative 3′ ends. APA contributes to the complexity of the transcriptome by generating isoforms that differ either in their coding sequence or in their 3′ untranslated regions (UTRs), thereby potentially regulating the function, stability, localization and translation efficiency of target RNAs. Here, we review our current understanding of the polyadenylation process and the latest progress in the identification of APA events, mechanisms that regulate poly(A) site selection, and biological processes and diseases resulting from APA.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Core players involved in cleavage and polyadenylation.
Figure 2: The four different APA types.
Figure 3: Biological processes that have been linked with broad APA modulation.
Figure 4: Mechanistic regulation of APA.
Figure 5: Therapeutic potential for intervention with APA.

Similar content being viewed by others

References

  1. Edmonds, M. & Abrams, R. Polynucleotide biosynthesis: formation of a sequence of adenylate units from adenosine triphosphate by an enzyme from thymus nuclei. J. Biol. Chem. 235, 1142–1149 (1960).

    Article  CAS  PubMed  Google Scholar 

  2. Proudfoot, N. J. Ending the message: poly(A) signals then and now. Genes Dev. 25, 1770–1782 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sachs, A. The role of poly(A) in the translation and stability of mRNA. Curr. Opin. Cell Biol. 2, 1092–1098 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Guhaniyogi, J. & Brewer, G. Regulation of mRNA stability in mammalian cells. Gene 265, 11–23 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. D'Ambrogio, A., Nagaoka, K. & Richter, J. D. Translational control of cell growth and malignancy by the CPEBs. Nature Rev. Cancer 13, 283–290 (2013).

    Article  CAS  Google Scholar 

  6. Martin, G., Gruber, A. R., Keller, W. & Zavolan, M. 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 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Fabian, M. R., Sonenberg, N. & Filipowicz, W. Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 79, 351–379 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Gautheret, D., Poirot, O., Lopez, F., Audic, S. & Claverie, J. M. Alternate polyadenylation in human mRNAs: a large-scale analysis by EST clustering. Genome Res. 8, 524–530 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Beaudoing, E., Freier, S., Wyatt, J. R., Claverie, J. M. & Gautheret, D. Patterns of variant polyadenylation signal usage in human genes. Genome Res. 10, 1001–1010 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brown, K. M. & Gilmartin, G. M. A mechanism for the regulation of pre-mRNA 3′ processing by human cleavage factor Im. Mol. Cell 12, 1467–1476 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Sandberg, R., Neilson, J. R., Sarma, A., Sharp, P. A. & Burge, C. B. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 320, 1643–1647 (2008). This paper presents the first genomic demonstration of the association between APA and proliferation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang, E. T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470–476 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pickrell, J. K. et al. Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464, 768–772 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sun, Y., Fu, Y., Li, Y. & Xu, A. Genome-wide alternative polyadenylation in animals: insights from high-throughput technologies. J. Mol. Cell. Biol. 4, 352–361 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Shi, Y. Alternative polyadenylation: new insights from global analyses. RNA 18, 2105–2117 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hoque, M. et al. Analysis of alternative cleavage and polyadenylation by 3′ region extraction and deep sequencing. Nature Methods 10, 133–139 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Zhang, H., Lee, J. Y. & Tian, B. Biased alternative polyadenylation in human tissues. Genome Biol. 6, R100 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Ji, Z., Lee, J. Y., Pan, Z., Jiang, B. & Tian, B. Progressive lengthening of 3′ untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development. Proc. Natl Acad. Sci. USA 106, 7028–7033 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hilgers, V. et al. Neural-specific elongation of 3′ UTRs during Drosophila development. Proc. Natl Acad. Sci. USA 108, 15864–15869 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shepard, P. J. et al. Complex and dynamic landscape of RNA polyadenylation revealed by PAS-seq. RNA 17, 761–772 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Smibert, P. et al. Global patterns of tissue-specific alternative polyadenylation in Drosophila. Cell Rep. 1, 277–289 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ulitsky, I. et al. Extensive alternative polyadenylation during zebrafish development. Genome Res. 22, 2054–2066 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ji, Z. & Tian, B. Reprogramming of 3′ untranslated regions of mRNAs by alternative polyadenylation in generation of pluripotent stem cells from different cell types. PLoS ONE 4, e8419 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Elkon, R. et al. E2F mediates enhanced alternative polyadenylation in proliferation. Genome Biol. 13, R59 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Timmusk, T. et al. Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 10, 475–489 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Lau, A. G. et al. Distinct 3′UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF). Proc. Natl Acad. Sci. USA 107, 15945–15950 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Flavell, S. W. et al. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60, 1022–1038 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Takagaki, Y. & Manley, J. L. Levels of polyadenylation factor CstF-64 control IgM heavy chain mRNA accumulation and other events associated with B cell differentiation. Mol. Cell 2, 761–771 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Takagaki, Y., Seipelt, R. L., Peterson, M. L. & Manley, J. L. The polyadenylation factor CstF-64 regulates alternative processing of IgM heavy chain pre-mRNA during B cell differentiation. Cell 87, 941–952 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Yao, C. et al. Transcriptome-wide analyses of CstF64–RNA interactions in global regulation of mRNA alternative polyadenylation. Proc. Natl Acad. Sci. USA 109, 18773–18778 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kubo, T., Wada, T., Yamaguchi, Y., Shimizu, A. & Handa, H. 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 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim, S. et al. Evidence that cleavage factor Im is a heterotetrameric protein complex controlling alternative polyadenylation. Genes Cells 15, 1003–1013 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Venkataraman, K., Brown, K. M. & Gilmartin, G. M. Analysis of a noncanonical poly(A) site reveals a tripartite mechanism for vertebrate poly(A) site recognition. Genes Dev. 19, 1315–1327 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nunes, N. M., Li, W., Tian, B. & Furger, A. A functional human poly(A) site requires only a potent DSE and an A-rich upstream sequence. EMBO J. 29, 1523–1536 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Maniatis, T. & Reed, R. An extensive network of coupling among gene expression machines. Nature 416, 499–506 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Perales, R. & Bentley, D. “Cotranscriptionality”: the transcription elongation complex as a nexus for nuclear transactions. Mol. Cell 36, 178–191 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shi, Y. et al. Molecular architecture of the human pre-mRNA 3′ processing complex. Mol. Cell 33, 365–376 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Di Giammartino, D. C., Nishida, K. & Manley, J. L. Mechanisms and consequences of alternative polyadenylation. Mol. Cell 43, 853–866 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nagaike, T. et al. Transcriptional activators enhance polyadenylation of mRNA precursors. Mol. Cell 41, 409–418 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rozenblatt-Rosen, O. et al. The tumor suppressor CDC73 functionally associates with CPSF and CstF 3′ mRNA processing factors. Proc. Natl Acad. Sci. USA 106, 755–760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Martincic, K., Alkan, S. A., Cheatle, A., Borghesi, L. & Milcarek, C. Transcription elongation factor ELL2 directs immunoglobulin secretion in plasma cells by stimulating altered RNA processing. Nature Immunol. 10, 1102–1109 (2009).

    Article  CAS  Google Scholar 

  44. Ji, Z. et al. Transcriptional activity regulates alternative cleavage and polyadenylation. Mol. Syst. Biol. 7, 534 (2011). This paper provides a nice demonstration of the interplay between APA and transcription.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Pinto, P. A. et al. RNA polymerase II kinetics in polo polyadenylation signal selection. EMBO J. 30, 2431–2444 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. de la Mata, M. et al. A slow RNA polymerase II affects alternative splicing in vivo. Mol. Cell 12, 525–532 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Spies, N., Nielsen, C. B., Padgett, R. A. & Burge, C. B. Biased chromatin signatures around polyadenylation sites and exons. Mol. Cell 36, 245–254 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wood, A. J. et al. A screen for retrotransposed imprinted genes reveals an association between X chromosome homology and maternal germ-line methylation. PLoS Genet. 3, e20 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Cowley, M., Wood, A. J., Bohm, S., Schulz, R. & Oakey, R. J. Epigenetic control of alternative mRNA processing at the imprinted Herc3/Nap1l5 locus. Nucleic Acids Res. 40, 8917–8926 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Millevoi, S. et al. An interaction between U2AF 65 and CF I(m) links the splicing and 3′ end processing machineries. EMBO J. 25, 4854–4864 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Millevoi, S. & Vagner, S. Molecular mechanisms of eukaryotic pre-mRNA 3′ end processing regulation. Nucleic Acids Res. 38, 2757–2774 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Licatalosi, D. D. et al. HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, 464–469 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kaida, D. et al. U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468, 664–668 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Berg, M. G. et al. U1 snRNP determines mRNA length and regulates isoform expression. Cell 150, 53–64 (2012). This paper characterizes the role of U1 in the interplay between APA and splicing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jenal, M. et al. The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites. Cell 149, 538–553 (2012). This paper identifies PABPN1 as a regulator of APA and provides the first link between a human genetic disorder (specifically, OPMD) and broad APA misregulation.

    Article  CAS  PubMed  Google Scholar 

  57. de Klerk, E. et al. Poly(A) binding protein nuclear 1 levels affect alternative polyadenylation. Nucleic Acids Res. 40, 9089–9101 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Hilgers, V., Lemke, S. B. & Levine, M. ELAV mediates 3′ UTR extension in the Drosophila nervous system. Genes Dev. 26, 2259–2264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mansfield, K. D. & Keene, J. D. Neuron-specific ELAV/Hu proteins suppress HuR mRNA during neuronal differentiation by alternative polyadenylation. Nucleic Acids Res. 40, 2734–2746 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Zhu, H., Zhou, H. L., Hasman, R. A. & Lou, H. Hu proteins regulate polyadenylation by blocking sites containing U-rich sequences. J. Biol. Chem. 282, 2203–2210 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Castelo-Branco, P. et al. Polypyrimidine tract binding protein modulates efficiency of polyadenylation. Mol. Cell. Biol. 24, 4174–4183 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Danckwardt, S. et al. Splicing factors stimulate polyadenylation via USEs at non-canonical 3′ end formation signals. EMBO J. 26, 2658–2669 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bava, F. A. et al. CPEB1 coordinates alternative 3′-UTR formation with translational regulation. Nature 495, 121–125 (2013). This paper shows that CPEB1, which is the key regulator of cytoplasmic polyadenylation, also regulates nuclear APA.

    Article  CAS  PubMed  Google Scholar 

  64. Danckwardt, S., Hentze, M. W. & Kulozik, A. E. 3′ end mRNA processing: molecular mechanisms and implications for health and disease. EMBO J. 27, 482–498 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Park, J. Y. et al. Comparative analysis of mRNA isoform expression in cardiac hypertrophy and development reveals multiple post-transcriptional regulatory modules. PLoS ONE 6, e22391 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mayr, C. & Bartel, D. P. Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673–684 (2009). This paper is the first to demonstrate an association between enhanced APA and cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fu, Y. et al. Differential genome-wide profiling of tandem 3′ UTRs among human breast cancer and normal cells by high-throughput sequencing. Genome Res. 21, 741–747 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lin, Y. et al. An in-depth map of polyadenylation sites in cancer. Nucleic Acids Res. 40, 8460–8471 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Morris, A. R. et al. Alternative cleavage and polyadenylation during colorectal cancer development. Clin. Cancer Res. 18, 5256–5266 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Galluzzi, L. et al. Prognostic impact of vitamin B6 metabolism in lung cancer. Cell Rep. 2, 257–269 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Akman, B. H., Can, T. & Erson-Bensan, A. E. Estrogen-induced upregulation and 3′-UTR shortening of CDC6. Nucleic Acids Res. 40, 10679–10688 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Vorlova, S. et al. Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation. Mol. Cell 43, 927–939 (2011). This is the first demonstration, to our knowledge, of the therapeutic potential for external manipulation of APA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ingolia, N. T., Brar, G. A., Rouskin, S., McGeachy, A. M. & Weissman, J. S. The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragments. Nature Protoc. 7, 1534–1550 (2012).

    Article  CAS  Google Scholar 

  74. Kole, R., Krainer, A. R. & Altman, S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nature Rev. Drug Discov. 11, 125–140 (2012).

    Article  CAS  Google Scholar 

  75. Yoon, O. K. & Brem, R. B. Noncanonical transcript forms in yeast and their regulation during environmental stress. RNA 16, 1256–1267 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Derti, A. et al. A quantitative atlas of polyadenylation in five mammals. Genome Res. 22, 1173–1183 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Beck, A. H. et al. 3′-end sequencing for expression quantification (3SEQ) from archival tumor samples. PLoS ONE 5, e8768 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Jan, C. H., Friedman, R. C., Ruby, J. G. & Bartel, D. P. Formation, regulation and evolution of Caenorhabditis elegans 3′UTRs. Nature 469, 97–101 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Ozsolak, F. et al. Comprehensive polyadenylation site maps in yeast and human reveal pervasive alternative polyadenylation. Cell 143, 1018–1029 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Friedel, C. C., Dolken, L., Ruzsics, Z., Koszinowski, U. H. & Zimmer, R. Conserved principles of mammalian transcriptional regulation revealed by RNA half-life. Nucleic Acids Res. 37, e115 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Colgan, D. F. & Manley, J. L. Mechanism and regulation of mRNA polyadenylation. Genes Dev. 11, 2755–2766 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Mandel, C. R., Bai, Y. & Tong, L. Protein factors in pre-mRNA 3′-end processing. Cell. Mol. Life Sci. 65, 1099–1122 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yang, Q., Coseno, M., Gilmartin, G. M. & Doublie, S. 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 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Higgs, D. R. et al. Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature 306, 398–400 (1983).

    Article  CAS  PubMed  Google Scholar 

  85. Orkin, S. H., Cheng, T. C., Antonarakis, S. E. & Kazazian, H. H. Jr. Thalassemia due to a mutation in the cleavage-polyadenylation signal of the human β-globin gene. EMBO J. 4, 453–456 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gieselmann, V., Polten, A., Kreysing, J. & von Figura, K. Arylsulfatase A pseudodeficiency: loss of a polyadenylylation signal and N-glycosylation site. Proc. Natl Acad. Sci. USA 86, 9436–9440 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Barth, M. L., Fensom, A. & Harris, A. Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain. Hum. Genet. 91, 73–77 (1993).

    Article  CAS  PubMed  Google Scholar 

  88. Bennett, C. L. et al. A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA–>AAUGAA) leads to the IPEX syndrome. Immunogenetics 53, 435–439 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Yasuda, M., Shabbeer, J., Osawa, M. & Desnick, R. J. Fabry disease: novel α-galactosidase A 3′-terminal mutations result in multiple transcripts due to aberrant 3′-end formation. Am. J. Hum. Genet. 73, 162–173 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by funds from the European Research Council (ERC), the Dutch cancer foundation (KWF), Horizon and the Netherlands Organisation for Scientific Research (VICI-NWO).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Reuven Agami.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

FURTHER INFORMATION

Reuven Agami's homepage

PowerPoint slides

Glossary

Photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation

(PAR-CLIP). A method for profiling RNA that is bound to a specific protein. Cells are grown in a medium containing 4-thiouridine or 6-thioguanosine, which, when incorporated into RNA, allows for efficient ultraviolet crosslinking to RNA-binding proteins. The immunoprecipitated protein–RNA complexes are then used to generate libraries for deep sequencing.

Serial analysis of gene expression

(SAGE). A method for quantitative and simultaneous analysis of a large number of transcripts; short sequence tags are isolated, concentrated and cloned; their sequencing reveals a gene expression pattern that is characteristic of the tissue or cell type from which the tags were isolated.

Induced pluripotent stem cells

(iPSCs). Pluripotent stem cells that are artificially derived from non-pluripotent cells, typically by genetic manipulation.

Striatal neurons

Neurons that lie in the striatum, which is an area of the brain involved in fine movements, emotion and cognition.

Hippocampal neurons

Neurons that lie in the hippocampus, which is a neurogenic region of the forebrain that has an important functions in learning and memory.

Immunoglobulin

(Ig). An antigen receptor molecule produced by B cells that consists of two heavy chains and two light chains.

Systematic evolution of ligands by exponential enrichment

(SELEX). In the context of RNA, this is a method for identifying consensus protein-binding sequences on RNA substrates by in vitro selection of short RNAs that bind preferentially to RNA-binding proteins.

Spliceosome

A ribonucleoprotein complex that is involved in splicing nuclear precursor mRNA (pre-mRNA). It is composed of five small nuclear ribonucleoproteins (snRNPs) and more than 50 non-snRNPs, which recognize and assemble on exon–intron boundaries to catalyse intron processing of the pre-mRNA.

Angiogenesis

The formation of new blood vessels from pre-existing ones. It is often associated with cell division and the subsequent sprouting of the endothelial cells that contribute to the growing blood vessel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Elkon, R., Ugalde, A. & Agami, R. Alternative cleavage and polyadenylation: extent, regulation and function. Nat Rev Genet 14, 496–506 (2013). https://doi.org/10.1038/nrg3482

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg3482

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research