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 polyadenylation of mRNA precursors

Key Points

  • Alternative polyadenylation (APA) is a widespread mechanism of gene regulation that generates distinct 3′ ends in transcripts made by RNA polymerase II.

  • APA is tissue specific and globally regulated in various conditions, such as cell proliferation and differentiation, and in response to extracellular cues.

  • APA occurring in 3′ untranslated regions (3′ UTRs) leads to the production of mRNA isoforms with different metabolisms and can also affect protein localization.

  • APA occurring in the region upstream of the 3′ UTR is often coupled with splicing and can lead to the production of distinct protein isoforms. It can also function by repressing gene expression.

  • APA is regulated by several known mechanisms, including regulation of the levels of core RNA-processing factors and other RNA-binding proteins, as well as by splicing and transcriptional dynamics.

Abstract

Alternative polyadenylation (APA) is an RNA-processing mechanism that generates distinct 3′ termini on mRNAs and other RNA polymerase II transcripts. It is widespread across all eukaryotic species and is recognized as a major mechanism of gene regulation. APA exhibits tissue specificity and is important for cell proliferation and differentiation. In this Review, we discuss the roles of APA in diverse cellular processes, including mRNA metabolism, protein diversification and protein localization, and more generally in gene regulation. We also discuss the molecular mechanisms underlying APA, such as variation in the concentration of core processing factors and RNA-binding proteins, as well as transcription-based regulation.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: 3′ UTR-APA.
Figure 2: UR-APA.
Figure 3: Regulation of APA.

References

  1. Richard, P. & Manley, J. L. Transcription termination by nuclear RNA polymerases. Genes Dev. 23, 1247–1269 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Marzluff, W. F., Wagner, E. J. & Duronio, R. J. Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nat. Rev. Genet. 9, 843–854 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. Zhao, J., Hyman, L. & Moore, C. Formation of mRNA 3′ ends in eukaryotes: mechanism, regulation, and interrelationships with other steps in mRNA synthesis. Microbiol. Mol. Biol. Rev. 63, 405–445 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shi, Y. & Manley, J. L. The end of the message: multiple protein–RNA interactions define the mRNA polyadenylation site. Genes Dev. 29, 889–897 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Edwalds-Gilbert, G., Veraldi, K. L. & Milcarek, C. Alternative poly(A) site selection in complex transcription units: means to an end? Nucleic Acids Res. 25, 2547–2561 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Barabino, S. M. & Keller, W. Last but not least: regulated poly(A) tail formation. Cell 99, 9–11 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. 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). This paper reports the first use of expressed sequence tags to identify APA sites genome-wide.

    Article  CAS  PubMed  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 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 

  13. Hoque, M. et al. Analysis of alternative cleavage and polyadenylation by 3′ region extraction and deep sequencing. Nat. Methods 10, 133–139 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Mayr, C. Evolution and biological roles of alternative 3′ UTRs. Trends Cell Biol. 26, 227–237 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Elkon, R., Ugalde, A. P. & Agami, R. Alternative cleavage and polyadenylation: extent, regulation and function. Nat. Rev. Genet. 14, 496–506 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hunt, A. G. Messenger RNA 3′ end formation in plants. Curr. Top. Microbiol. Immunol. 326, 151–177 (2008).

    CAS  PubMed  Google Scholar 

  20. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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 is the first report that global changes in APA occur as a consequence of changes in cell proliferation, specifically demonstrating the use of proximal 3′ UTR PASs during the activation of T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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). This article describes global APA regulation in embryonic development, connecting polyadenylation activity with APA during cell differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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 publication reports a connection between 3′ UTR shortening, especially in the transcripts of several proto-oncogenes, and cell transformation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nam, J. W. et al. Global analyses of the effect of different cellular contexts on microRNA targeting. Mol. Cell 53, 1031–1043 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hoffman, Y. et al. 3′ UTR shortening potentiates microRNA-based repression of pro-differentiation genes in proliferating human cells. PLoS Genet. 12, e1005879 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Garneau, N. L., Wilusz, J. & Wilusz, C. J. The highways and byways of mRNA decay. Nat. Rev. Mol. Cell Biol. 8, 113–126 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Graham, R. R. et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc. Natl Acad. Sci. USA 104, 6758–6763 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gong, C. & Maquat, L. E. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature 470, 284–288 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hogg, J. R. & Goff, S. P. Upf1 senses 3′ UTR length to potentiate mRNA decay. Cell 143, 379–389 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Spies, N., Burge, C. B. & Bartel, D. P. 3′ UTR-isoform choice has limited influence on the stability and translational efficiency of most mRNAs in mouse fibroblasts. Genome Res. 23, 2078–2090 (2013). This report presents a global analysis of the different effects of short and long 3′ UTRs on mRNA decay and translation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Geisberg, J. V., Moqtaderi, Z., Fan, X., Ozsolak, F. & Struhl, K. Global analysis of mRNA isoform half-lives reveals stabilizing and destabilizing elements in yeast. Cell 156, 812–824 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tycowski, K. T., Shu, M. D. & Steitz, J. A. Myriad triple-helix-forming structures in the transposable element RNAs of plants and fungi. Cell Rep. 15, 1266–1276 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee, J. E., Lee, J. Y., Wilusz, J., Tian, B. & Wilusz, C. J. Systematic analysis of cis-elements in unstable mRNAs demonstrates that CUGBP1 is a key regulator of mRNA decay in muscle cells. PLoS ONE 5, e11201 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Floor, S. N. & Doudna, J. A. Tunable protein synthesis by transcript isoforms in human cells. eLife 5, e10921 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Neve, J. et al. Subcellular RNA profiling links splicing and nuclear DICER1 to alternative cleavage and polyadenylation. Genome Res. 26, 24–35 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Djebali, S. et al. Landscape of transcription in human cells. Nature 489, 101–108 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen, L. L. & Carmichael, G. G. Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA. Mol. Cell 35, 467–478 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Martin, K. C. & Ephrussi, A. mRNA localization: gene expression in the spatial dimension. Cell 136, 719–730 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. An, J. J. et al. Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134, 175–187 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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 

  42. Yudin, D. et al. Localized regulation of axonal RanGTPase controls retrograde injury signaling in peripheral nerve. Neuron 59, 241–252 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Taliaferro, J. M. et al. Distal alternative last exons localize mRNAs to neural projections. Mol. Cell 61, 821–833 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Loya, A. et al. The 3′-UTR mediates the cellular localization of an mRNA encoding a short plasma membrane protein. RNA 14, 1352–1365 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Reid, D. W. & Nicchitta, C. V. Diversity and selectivity in mRNA translation on the endoplasmic reticulum. Nat. Rev. Mol. Cell Biol. 16, 221–231 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Berkovits, B. D. & Mayr, C. Alternative 3′ UTRs act as scaffolds to regulate membrane protein localization. Nature 522, 363–367 (2015). This work discovers a novel mechanism by which the aUTR of a transcript functions as a scaffold for the assembly of specific protein complexes, which then modulate the subcellular localization of the encoded protein.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Vasudevan, S., Peltz, S. W. & Wilusz, C. J. Non-stop decay — a new mRNA surveillance pathway. Bioessays 24, 785–788 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Yao, P. et al. Coding region polyadenylation generates a truncated tRNA synthetase that counters translation repression. Cell 149, 88–100 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Amara, S. G., Jonas, V., Rosenfeld, M. G., Ong, E. S. & Evans, R. M. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298, 240–244 (1982).

    Article  CAS  PubMed  Google Scholar 

  51. Alt, F. W. et al. Synthesis of secreted and membrane-bound immunoglobulin mu heavy chains is directed by mRNAs that differ at their 3′ ends. Cell 20, 293–301 (1980).

    Article  CAS  PubMed  Google Scholar 

  52. Davis, M. J. et al. Differential use of signal peptides and membrane domains is a common occurrence in the protein output of transcriptional units. PLoS Genet. 2, e46 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Vorlova, S. et al. Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation. Mol. Cell 43, 927–939 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Di Giammartino, D. C. et al. RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs. Gene Dev. 28, 2248–2260 (2014).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. Mbita, Z. et al. De-regulation of the RBBP6 isoform 3/DWNN in human cancers. Mol. Cell Biochem. 362, 249–262 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Pan, Z. et al. An intronic polyadenylation site in human and mouse CstF-77 genes suggests an evolutionarily conserved regulatory mechanism. Gene 366, 325–334 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Luo, W. et al. The conserved intronic cleavage and polyadenylation site of CstF-77 gene imparts control of 3′ end processing activity through feedback autoregulation and by U1 snRNP. PLoS Genet. 9, e1003613 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Audibert, A. & Simonelig, M. Autoregulation at the level of mRNA 3′ end formation of the suppressor of forked gene of Drosophila melanogaster is conserved in Drosophila virilis. Proc. Natl Acad. Sci. USA 95, 14302–14307 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhao, W. & Manley, J. L. Complex alternative RNA processing generates an unexpected diversity of poly(A) polymerase isoforms. Mol. Cell. Biol. 16, 2378–2386 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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). This study uncovers a mechanism of APA regulation in which increased expression of a core polyadenylation factor, CSTF64, during B cell differentiation shifts PAS usage to an upstream site in the IgM heavy chain pre-mRNA.

    Article  CAS  PubMed  Google Scholar 

  61. Yao, C. et al. Overlapping and distinct functions of CstF64 and CstF64τ in mammalian mRNA 3′ processing. RNA 19, 1781–1790 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Li, W. et al. Systematic profiling of poly(A)+ transcripts modulated by core 3′ end processing and splicing factors reveals regulatory rules of alternative cleavage and polyadenylation. PLoS Genet. 11, e1005166 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Xia, Z. et al. Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3′-UTR landscape across seven tumour types. Nat. Commun. 5, 5274 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. 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 

  65. Lackford, B. et al. Fip1 regulates mRNA alternative polyadenylation to promote stem cell self-renewal. EMBO J. 33, 878–889 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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 

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

    Article  CAS  PubMed  Google Scholar 

  68. 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 

  69. Yang, Q., Gilmartin, G. M. & Doublié, S. The structure of human Cleavage Factor Im hints at functions beyond UGUA-specific RNA binding: a role in alternative polyadenylation and a potential link to 5′ capping and splicing. RNA Biol. 8, 748–753 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Masamha, C. P. et al. CFIm25 links alternative polyadenylation to glioblastoma tumour suppression. Nature 510, 412–416 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gennarino, V. A. et al. NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation. eLife 4, e10782 (2015).

    Article  PubMed Central  Google Scholar 

  72. Kuhn, U. et al. 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 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Jenal, M. et al. The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites. Cell 149, 538–553 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. 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 

  75. Bresson, S. M. & Conrad, N. K. The human nuclear poly(A)-binding protein promotes RNA hyperadenylation and decay. PLoS Genet. 9, e1003893 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Beaulieu, Y. B., Kleinman, C. L., Landry-Voyer, A. M., Majewski, J. & Bachand, F. Polyadenylation-dependent control of long noncoding RNA expression by the poly(A)-binding protein nuclear 1. PLoS Genet. 8, e1003078 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bresson, S. M., Hunter, O. V., Hunter, A. C. & Conrad, N. K. Canonical poly(A) polymerase activity promotes the decay of a wide variety of mammalian nuclear RNAs. PLoS Genet. 11, e1005610 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Thomas, P. E. et al. Genome-wide control of polyadenylation site choice by CPSF30 in Arabidopsis. Plant Cell 24, 4376–4388 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Niwa, M., Rose, S. D. & Berget, S. M. In vitro polyadenylation is stimulated by the presence of an upstream intron. Genes Dev. 4, 1552–1559 (1990).

    Article  CAS  PubMed  Google Scholar 

  80. 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 

  81. Lutz, C. S. et al. Interaction between the U1 snRNP-A protein and the 160-kD subunit of cleavage-polyadenylation specificity factor increases polyadenylation efficiency in vitro. Genes Dev. 10, 325–337 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Kyburz, A., Friedlein, A., Langen, H. & Keller, W. 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 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gunderson, S. I., Polycarpou-Schwarz, M. & Mattaj, I. W. U1 snRNP inhibits pre-mRNA polyadenylation through a direct interaction between U1 70K and poly(A) polymerase. Mol. Cell 1, 255–264 (1998).

    Article  CAS  PubMed  Google Scholar 

  85. Kaida, D. et al. U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468, 664–668 (2010). This article describes a global activity of U1 snRNP in suppressing promoter-proximal PASs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Berg, M. G. et al. U1 snRNP determines mRNA length and regulates isoform expression. Cell 150, 53–64 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Engreitz, J. M. et al. RNA−RNA interactions enable specific targeting of noncoding RNAs to nascent pre-mRNAs and chromatin sites. Cell 159, 188–199 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wahl, M. C., Will, C. L. & Luhrmann, R. The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701–718 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Devany, E. et al. Intronic cleavage and polyadenylation regulates gene expression during DNA damage response through U1 snRNA. Cell Discov. 2, 16013 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Licatalosi, D. D. et al. HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, 464–469 (2008). This is the first demonstration that a splicing-regulatory RBP, NOVA, can also regulate APA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zheng, D. & Tian, B. RNA-binding proteins in regulation of alternative cleavage and polyadenylation. Adv. Exp. Med. Biol. 825, 97–127 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. 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 

  93. Oktaba, K. et al. ELAV links paused Pol II to alternative polyadenylation in the Drosophila nervous system. Mol. Cell 57, 341–348 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. 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 

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

    Article  CAS  PubMed  Google Scholar 

  96. 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 

  97. Manley, J. L. & Tacke, R. SR proteins and splicing control. Genes Dev. 10, 1569–1579 (1996).

    Article  CAS  PubMed  Google Scholar 

  98. Howard, J. M. & Sanford, J. R. The RNAissance family: SR proteins as multifaceted regulators of gene expression. Wiley Interdiscip. Rev. RNA 6, 93–110 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Muller-McNicoll, M. et al. SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export. Genes Dev. 30, 553–566 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Tran, D. D. et al. THOC5 controls 3′ end-processing of immediate early genes via interaction with polyadenylation specific factor 100 (CPSF100). Nucleic Acids Res. 42, 12249–12260 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Johnson, S. A., Kim, H., Erickson, B. & Bentley, D. L. The export factor Yra1 modulates mRNA 3′ end processing. Nat. Struct. Mol. Biol. 18, 1164–1171 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ling, S. C., Polymenidou, M. & Cleveland, D. W. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79, 416–438 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Masuda, A. et al. Position-specific binding of FUS to nascent RNA regulates mRNA length. Genes Dev. 29, 1045–1057 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Schwartz, J. C. et al. FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2. Genes Dev. 26, 2690–2695 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hoell, J. I. et al. RNA targets of wild-type and mutant FET family proteins. Nat. Struct. Mol. Biol. 18, 1428–1431 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Prudencio, M. et al. Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nat. Neurosci. 18, 1175–1182 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lee, Y. B. et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep. 5, 1178–1186 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Batra, R. et al. Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA-mediated disease. Mol. Cell 56, 311–322 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Naftelberg, S., Schor, I. E., Ast, G. & Kornblihtt, A. R. Regulation of alternative splicing through coupling with transcription and chromatin structure. Annu. Rev. Biochem. 84, 165–198 (2015).

    Article  CAS  PubMed  Google Scholar 

  110. Yonaha, M. & Proudfoot, N. J. Specific transcriptional pausing activates polyadenylation in a coupled in vitro system. Mol. Cell 3, 593–600 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Cui, Y. & Denis, C. L. In vivo evidence that defects in the transcriptional elongation factors RPB2, TFIIS, and SPT5 enhance upstream poly(A) site utilization. Mol. Cell. Biol. 23, 7887–7901 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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. Nat. Immunol. 10, 1102–1109 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 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 

  114. Rosonina, E., Bakowski, M. A., McCracken, S. & Blencowe, B. J. Transcriptional activators control splicing and 3′ -end cleavage levels. J. Biol. Chem. 278, 43034–43040 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ji, Z. et al. Transcriptional activity regulates alternative cleavage and polyadenylation. Mol. Syst. Biol. 7, 534 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Ni, T. et al. Distinct polyadenylation landscapes of diverse human tissues revealed by a modified PA-seq strategy. BMC Genomics 14, 615 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Glover-Cutter, K., Kim, S., Espinosa, J. & Bentley, D. L. RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes. Nat. Struct. Mol. Biol. 15, 71–78 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. 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 

  120. 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 

  121. Calvo, O. & Manley, J. L. Strange bedfellows: polyadenylation factors at the promoter. Genes Dev. 17, 1321–1327 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Uhlmann, T., Boeing, S., Lehmbacher, M. & Meisterernst, M. The VP16 activation domain establishes an active mediator lacking CDK8 in vivo. J. Biol. Chem. 282, 2163–2173 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Yang, Y. et al. PAF complex plays novel subunit-specific roles in alternative cleavage and polyadenylation. PLoS Genet. 12, e1005794 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Yu, M. et al. RNA polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA polymerase II. Science 350, 1383–1386 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Jiang, C. & Pugh, B. F. Nucleosome positioning and gene regulation: advances through genomics. Nat. Rev. Genet. 10, 161–172 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kaplan, N. et al. The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458, 362–366 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. 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 

  128. Grosso, A. R., de Almeida, S. F., Braga, J. & Carmo-Fonseca, M. Dynamic transitions in RNA polymerase II density profiles during transcription termination. Genome Res. 22, 1447–1456 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Li, W. et al. Alternative cleavage and polyadenylation in spermatogenesis connects chromatin regulation with post-transcriptional control. BMC Biol. 14, 6 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Ke, S. et al. A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation. Genes Dev. 29, 2037–2053 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Eckmann, C. R., Rammelt, C. & Wahle, E. Control of poly(A) tail length. Wiley Interdiscip. Rev. RNA 2, 348–361 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Schmidt, M. J. & Norbury, C. J. Polyadenylation and beyond: emerging roles for noncanonical poly(A) polymerases. Wiley Interdiscip. Rev. RNA 1, 142–151 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Mendez, R. & Richter, J. D. Translational control by CPEB: a means to the end. Nat. Rev. Mol. Cell Biol. 2, 521–529 (2001).

    Article  CAS  PubMed  Google Scholar 

  134. Subtelny, A. O., Eichhorn, S. W., Chen, G. R., Sive, H. & Bartel, D. P. Poly(A)-tail profiling reveals an embryonic switch in translational control. Nature 508, 66–71 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chang, H., Lim, J., Ha, M. & Kim, V. N. TAIL-seq: genome-wide determination of poly(A) tail length and 3′ end modifications. Mol. Cell 53, 1044–1052 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Wang, K. C. & Chang, H. Y. Molecular mechanisms of long noncoding RNAs. Mol. Cell 43, 904–914 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Naganuma, T. et al. Alternative 3′-end processing of long noncoding RNA initiates construction of nuclear paraspeckles. EMBO J. 31, 4020–4034 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Higgs, D. R. et al. α-Thalassaemia caused by a polyadenylation signal mutation. Nature 306, 398–400 (1983).

    Article  CAS  PubMed  Google Scholar 

  139. Prasad, M. K. et al. A polymorphic 3′ UTR element in ATP1B1 regulates alternative polyadenylation and is associated with blood pressure. PLoS ONE 8, e76290 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Singh, P. et al. Global changes in processing of mRNA 3′ untranslated regions characterize clinically distinct cancer subtypes. Cancer Res. 69, 9422–9430 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Creemers, E. E. et al. Genome-wide polyadenylation maps reveal dynamic mRNA 3′-end formation in the failing human heart. Circ. Res. 118, 433–438 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Soetanto, R. et al. Role of miRNAs and alternative mRNA 3′-end cleavage and polyadenylation of their mRNA targets in cardiomyocyte hypertrophy. Biochim. Biophys. Acta 1859, 744–756 (2016).

    Article  CAS  PubMed  Google Scholar 

  143. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Cheng, Y., Miura, R. M. & Tian, B. Prediction of mRNA polyadenylation sites by support vector machine. Bioinformatics 22, 2320–2325 (2006).

    Article  CAS  PubMed  Google Scholar 

  146. 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 

  147. Sheets, M. D., Ogg, S. C. & Wickens, M. P. Point mutations in AAUAAA and the poly (A) addition site: effects on the accuracy and efficiency of cleavage and polyadenylation in vitro. Nucleic Acids Res. 18, 5799–5805 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Shi, Y. et al. Molecular architecture of the human pre-mRNA 3′ processing complex. Mol. Cell 33, 365–376 (2009). This report details the purification of an active polyadenylation complex on substrate RNA and the identification of more than 80 core and associated proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Chan, S. L. et al. CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3′ processing. Genes Dev. 28, 2370–2380 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Schonemann, L. et al. Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33. Genes Dev. 28, 2381–2393 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Kaufmann, I., Martin, G., Friedlein, A., Langen, H. & Keller, W. Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase. EMBO J. 23, 616–626 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Takagaki, Y. & Manley, J. L. RNA recognition by the human polyadenylation factor CstF. Mol. Cell. Biol. 17, 3907–3914 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Chen, F. & Wilusz, J. Auxiliary downstream elements are required for efficient polyadenylation of mammalian pre-mRNAs. Nucleic Acids Res. 26, 2891–2898 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Mandel, C. R. et al. Polyadenylation factor CPSF-73 is the pre-mRNA 3′-end-processing endonuclease. Nature 444, 953–956 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Bai, Y. et al. Crystal structure of murine CstF-77: dimeric association and implications for polyadenylation of mRNA precursors. Mol. Cell 25, 863–875 (2007).

    Article  CAS  PubMed  Google Scholar 

  156. Yang, Q., Gilmartin, G. M. & Doublié, S. Structural basis of UGUA recognition by the Nudix protein CFIm25 and implications for a regulatory role in mRNA 3′ processing. Proc. Natl Acad. Sci. USA 107, 10062–10067 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Hunt, A. G., Xing, D. & Li, Q. Q. Plant polyadenylation factors: conservation and variety in the polyadenylation complex in plants. BMC Genomics 13, 641 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Zhang, H., Lee, J. Y. & Tian, B. Biased alternative polyadenylation in human tissues. Genome Biol. 6, R100 (2005). This is the first demonstration that isoforms using proximal and distal PASs are expressed with bias in certain tissues, for example in the brain and blood.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Lianoglou, S., Garg, V., Yang, J. L., Leslie, C. S. & Mayr, C. Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression. Genes Dev. 27, 2380–2396 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Liu, D. et al. Systematic variation in mRNA 3′-processing signals during mouse spermatogenesis. Nucleic Acids Res. 35, 234–246 (2007).

    Article  CAS  PubMed  Google Scholar 

  162. 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 

  163. Lee, J. Y., Ji, Z. & Tian, B. Phylogenetic analysis of mRNA polyadenylation sites reveals a role of transposable elements in evolution of the 3′-end of genes. Nucleic Acids Res. 36, 5581–5590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 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 

  165. Dai, W. et al. A post-transcriptional mechanism pacing expression of neural genes with precursor cell differentiation status. Nat. Commun. 6, 7576 (2015).

    Article  PubMed  Google Scholar 

  166. Dass, B. et al. Loss of polyadenylation protein τCstF-64 causes spermatogenic defects and male infertility. Proc. Natl Acad. Sci. USA 104, 20374–20379 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Sartini, B. L., Wang, H., Wang, W., Millette, C. F. & Kilpatrick, D. L. Pre-messenger RNA cleavage factor I (CFIm): potential role in alternative polyadenylation during spermatogenesis. Biol. Reprod. 78, 472–482 (2008).

    Article  CAS  PubMed  Google Scholar 

  168. Soumillon, M. et al. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. Cell Rep. 3, 2179–2190 (2013).

    Article  CAS  PubMed  Google Scholar 

  169. Zhang, P. et al. MIWI and piRNA-mediated cleavage of messenger RNAs in mouse testes. Cell Res. 25, 193–207 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Goh, W. S. et al. piRNA-directed cleavage of meiotic transcripts regulates spermatogenesis. Genes Dev. 29, 1032–1044 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Watanabe, T., Cheng, E. C., Zhong, M. & Lin, H. Retrotransposons and pseudogenes regulate mRNAs and lncRNAs via the piRNA pathway in the germline. Genome Res. 25, 368–380 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Bao, J. et al. UPF2-dependent nonsense-mediated mRNA decay pathway is essential for spermatogenesis by selectively eliminating longer 3′ UTR transcripts. PLoS Genet. 12, e1005863 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Fanourgakis, G., Lesche, M., Akpinar, M., Dahl, A. & Jessberger, R. Chromatoid body protein TDRD6 supports long 3′ UTR triggered nonsense mediated mRNA decay. PLoS Genet. 12, e1005857 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Gruber, A. R. et al. Global 3′ UTR shortening has a limited effect on protein abundance in proliferating T cells. Nat. Commun. 5, 5465 (2014).

    Article  CAS  PubMed  Google Scholar 

  175. 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 

  176. 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 

  177. 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 

  178. Chang, J. W. et al. mRNA 3′-UTR shortening is a molecular signature of mTORC1 activation. Nat. Commun. 6, 7218 (2015).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank members of their laboratories for helpful discussions, and I. Boluck for assistance with manuscript preparation. Work in the authors' laboratories was funded by grants GM84089 (B.T.), and GM28983 and GM118136 (J.L.M.) from the US National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Bin Tian or James L. Manley.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (box)

Variation in alternative polyadenylation across species (PDF 122 kb)

PowerPoint slides

Glossary

PUF protein

(Pumilio and FBF homology family protein). A member of a family of RNA-binding proteins that regulate aspects of mRNA metabolism by binding to specific sequences in 3′ untranslated regions.

STAU1-mediated mRNA decay

An mRNA decay mechanism in which RNA structures in the 3′ untranslated region interact with double-stranded RNA-binding protein Staufen homologue 1 (STAU1) to mediate mRNA decay.

AU-rich element-mediated decay

mRNA decay elicited by the presence of AU-rich elements (AREs) in the 3′ untranslated region.

PIWI-interacting RNAs

Small non-coding RNAs that form RNA–protein complexes with PIWI proteins to silence transposable elements in germline cells of metazoans.

Non-stop decay

An mRNA decay mechanism that specifically degrades mRNAs without a stop codon.

Exosome

A nuclear or cytoplasmic multiprotein complex that degrades mRNAs through the activity of 3′-to-5′ exoribonucleases.

Non-canonical PAPs

(Non-canonical poly(A) polymerases). Enzymes that have distinct structural features and are capable of synthesizing poly(A) tails but are not typically associated with the polyadenylation machinery.

Paused Pol II

(Paused RNA polymerase II). Pol II that has paused in the promoter-proximal region of the mRNA and is poised for productive elongation.

Paraspeckle

A dynamic nuclear compartment composed of RNA-binding proteins and RNAs. The functions of paraspeckles are not entirely clear.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tian, B., Manley, J. Alternative polyadenylation of mRNA precursors. Nat Rev Mol Cell Biol 18, 18–30 (2017). https://doi.org/10.1038/nrm.2016.116

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2016.116

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing