Alternative polyadenylation of mRNA precursors

Nature Reviews Molecular Cell Biology

Volumn 18, Issue 1, 2016, Pages 18-30

  Tian, Bin ^a   Manley, James L ^b  

^a RUTGERS NEW JERSEY MEDICAL SCHOOL   (United States)

^b Columbia University ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CORE PROTEIN; MESSENGER RNA PRECURSOR; RNA BINDING PROTEIN; SMALL NUCLEAR RIBONUCLEOPROTEIN; 3' UNTRANSLATED REGION; MESSENGER RNA; RNA PRECURSOR;

3' UNTRANSLATED REGION; CELL FUNCTION; EXON; GENE CONTROL; GENE REPRESSION; HUMAN; MOLECULAR MECHANICS; NUCLEAR EXPORT SIGNAL; NUCLEAR LOCALIZATION SIGNAL; POLYADENYLATION; PRIORITY JOURNAL; PROTEIN LOCALIZATION; REVIEW; RNA METABOLISM; RNA SPLICING; RNA STABILITY; RNA TRANSLATION; TRANSCRIPTION REGULATION; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; NUCLEOCYTOPLASMIC TRANSPORT;

3' UNTRANSLATED REGIONS; ACTIVE TRANSPORT, CELL NUCLEUS; EXONS; GENE EXPRESSION REGULATION; HUMANS; POLYADENYLATION; RIBONUCLEOPROTEIN, U1 SMALL NUCLEAR; RNA PRECURSORS; RNA STABILITY; RNA, MESSENGER; RNA-BINDING PROTEINS;

EID: 84988719252     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm.2016.116     Document Type: Review

References (178)

1. Richard, P. & Manley, J. L. Transcription termination by nuclear RNA polymerases. Genes Dev. 23, 1247-1269 (2009).
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).
3. Tian, B. & Graber, J. H. Signals for pre-mRNA cleavage and polyadenylation. Wiley Interdiscip. Rev. RNA 3, 385-396 (2012).
4. Mandel, C. R., Bai, Y. & Tong, L. Protein factors in pre-mRNA 3'-end processing. Cell. Mol. Life Sci. 65, 1099-1122 (2008).
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).
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).
7. Colgan, D. F. & Manley, J. L. Mechanism and regulation of mRNA polyadenylation. Genes Dev. 11, 2755-2766 (1997).
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).
9. Barabino, S. M. & Keller, W. Last but not least: regulated poly(A) tail formation. Cell 99, 9-11 (1999).
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).
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).
12. Derti, A. et al. A quantitative atlas of polyadenylation in five mammals. Genome Res. 22, 1173-1183 (2012).
13. Hoque, M. et al. Analysis of alternative cleavage and polyadenylation by 3' region extraction and deep sequencing. Nat. Methods 10, 133-139 (2013).
14. Mayr, C. Evolution and biological roles of alternative 3' UTRs. Trends Cell Biol. 26, 227-237 (2016).
15. Proudfoot, N. J. Ending the message: poly(A) signals then and now. Genes Dev. 25, 1770-1782 (2011).
16. Elkon, R., Ugalde, A. P. & Agami, R. Alternative cleavage and polyadenylation: extent, regulation and function. Nat. Rev. Genet. 14, 496-506 (2013).
17. Di Giammartino, D. C., Nishida, K. & Manley, J. L. Mechanisms and consequences of alternative polyadenylation. Mol. Cell 43, 853-866 (2011).
18. Tian, B. & Manley, J. L. Alternative cleavage and polyadenylation: the long and short of it. Trends Biochem. Sci. 38, 312-320 (2013).
19. Hunt, A. G. Messenger RNA 3' end formation in plants. Curr. Top. Microbiol. Immunol. 326, 151-177 (2008).
20. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215-233 (2009).
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).
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).
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).
24. Nam, J. W. et al. Global analyses of the effect of different cellular contexts on microRNA targeting. Mol. Cell 53, 1031-1043 (2014).
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).
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).
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).
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).
29. Hogg, J. R. & Goff, S. P. Upf1 senses 3' UTR length to potentiate mRNA decay. Cell 143, 379-389 (2010).
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).
31. Ulitsky, I. et al. Extensive alternative polyadenylation during zebrafish development. Genome Res. 22, 2054-2066 (2012).
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).
33. Tycowski, K. T., Shu, M. D. & Steitz, J. A. Myriad triplehelix- forming structures in the transposable element RNAs of plants and fungi. Cell Rep. 15, 1266-1276 (2016).
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).
35. Floor, S. N. & Doudna, J. A. Tunable protein synthesis by transcript isoforms in human cells. eLife 5, e10921 (2016).
36. Neve, J. et al. Subcellular RNA profiling links splicing and nuclear DICER1 to alternative cleavage and polyadenylation. Genome Res. 26, 24-35 (2016).
37. Djebali, S. et al. Landscape of transcription in human cells. Nature 489, 101-108 (2012).
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).
39. Martin, K. C. & Ephrussi, A. mRNA localization: gene expression in the spatial dimension. Cell 136, 719-730 (2009).
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).
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).
42. Yudin, D. et al. Localized regulation of axonal RanGTPase controls retrograde injury signaling in peripheral nerve. Neuron 59, 241-252 (2008).
43. Taliaferro, J. M. et al. Distal alternative last exons localize mRNAs to neural projections. Mol. Cell 61, 821-833 (2016).
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).
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).
46. Berkovits, B. D. & Mayr, C. Alternative 3' UTRs act as scaffolds to regulate membrane protein localization. Nature 522, 363-367 (2015).
47. Vasudevan, S., Peltz, S. W. & Wilusz, C. J. Non-stop decay - a new mRNA surveillance pathway. Bioessays 24, 785-788 (2002).
48. Yao, P. et al. Coding region polyadenylation generates a truncated tRNA synthetase that counters translation repression. Cell 149, 88-100 (2012).
49. Elkon, R. et al. E2F mediates enhanced alternative polyadenylation in proliferation. Genome Biol. 13, R59 (2012).
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).
51. Alt, F. W. et al. Synthesis of secreted and membranebound immunoglobulin mu heavy chains is directed by mRNAs that differ at their 3' ends. Cell 20, 293-301 (1980).
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).
53. Vorlova, S. et al. Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation. Mol. Cell 43, 927-939 (2011).
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).
55. Mbita, Z. et al. De-regulation of the RBBP6 isoform 3/DWNN in human cancers. Mol. Cell Biochem. 362, 249-262 (2012).
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).
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).
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).
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).
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).
61. Yao, C. et al. Overlapping and distinct functions of CstF64 and CstF64 in mammalian mRNA 3' processing. RNA 19, 1781-1790 (2013).
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).
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).
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).
65. Lackford, B. et al. Fip1 regulates mRNA alternative polyadenylation to promote stem cell self-renewal. EMBO J. 33, 878-889 (2014).
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).
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).
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).
69. Yang, Q., Gilmartin, G. M. & Doublie, 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).
70. Masamha, C. P. et al. CFIm25 links alternative polyadenylation to glioblastoma tumour suppression. Nature 510, 412-416 (2014).
71. Gennarino, V. A. et al. NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation. eLife 4, e10782 (2015).
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).
73. Jenal, M. et al. The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites. Cell 149, 538-553 (2012).
74. de Klerk, E. et al. Poly(A) binding protein nuclear 1 levels affect alternative polyadenylation. Nucleic Acids Res. 40, 9089-9101 (2012).
75. Bresson, S. M. & Conrad, N. K. The human nuclear poly(A)-binding protein promotes RNA hyperadenylation and decay. PLoS Genet. 9, e1003893 (2013).
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).
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).
78. Thomas, P. E. et al. Genome-wide control of polyadenylation site choice by CPSF30 in Arabidopsis. Plant Cell 24, 4376-4388 (2012).
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).
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).
81. Lutz, C. S. et al. Interaction between the U1 snRNP-A protein and the 160-kD subunit of cleavagepolyadenylation specificity factor increases polyadenylation efficiency in vitro. Genes Dev. 10, 325-337 (1996).
82. Kyburz, A., Friedlein, A., Langen, H. & Keller, W. Direct interactions between subunits of CPSF and the U2 snRNP contribute to the coupling of premRNA 3' end processing and splicing. Mol. Cell 23, 195-205 (2006).
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).
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).
85. Kaida, D. et al. U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468, 664-668 (2010).
86. Berg, M. G. et al. U1 snRNP determines mRNA length and regulates isoform expression. Cell 150, 53-64 (2012).
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).
88. Wahl, M. C., Will, C. L. & Luhrmann, R. The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701-718 (2009).
89. Devany, E. et al. Intronic cleavage and polyadenylation regulates gene expression during DNA damage response through U1 snRNA. Cell Discov. 2, 16013 (2016).
90. Licatalosi, D. D. et al. HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, 464-469 (2008).
91. Zheng, D. & Tian, B. RNA-binding proteins in regulation of alternative cleavage and polyadenylation. Adv. Exp. Med. Biol. 825, 97-127 (2014).
92. Hilgers, V., Lemke, S. B. & Levine, M. ELAV mediates 3' UTR extension in the Drosophila nervous system. Genes Dev. 26, 2259-2264 (2012).
93. Oktaba, K. et al. ELAV links paused Pol II to alternative polyadenylation in the Drosophila nervous system. Mol. Cell 57, 341-348 (2015).
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).
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).
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).
97. Manley, J. L. & Tacke, R. SR proteins and splicing control. Genes Dev. 10, 1569-1579 (1996).
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).
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).
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).
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).
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).
103. Masuda, A. et al. Position-specific binding of FUS to nascent RNA regulates mRNA length. Genes Dev. 29, 1045-1057 (2015).
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).
105. Hoell, J. I. et al. RNA targets of wild-type and mutant FET family proteins. Nat. Struct. Mol. Biol. 18, 1428-1431 (2011).
106. Prudencio, M. et al. Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nat. Neurosci. 18, 1175-1182 (2015).
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).
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).
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).
110. Yonaha, M. & Proudfoot, N. J. Specific transcriptional pausing activates polyadenylation in a coupled in vitro system. Mol. Cell 3, 593-600 (1999).
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).
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).
113. Pinto, P. A. et al. RNA polymerase II kinetics in polo polyadenylation signal selection. EMBO J. 30, 2431-2444 (2011).
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).
115. Nagaike, T. et al. Transcriptional activators enhance polyadenylation of mRNA precursors. Mol. Cell 41, 409-418 (2011).
116. Ji, Z. et al. Transcriptional activity regulates alternative cleavage and polyadenylation. Mol. Syst. Biol. 7, 534 (2011).
117. Ni, T. et al. Distinct polyadenylation landscapes of diverse human tissues revealed by a modified PA-seq strategy. BMC Genomics 14, 615 (2013).
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).
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).
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).
121. Calvo, O. & Manley, J. L. Strange bedfellows: polyadenylation factors at the promoter. Genes Dev. 17, 1321-1327 (2003).
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).
123. Yang, Y. et al. PAF complex plays novel subunit-specific roles in alternative cleavage and polyadenylation. PLoS Genet. 12, e1005794 (2016).
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).
125. Jiang, C. & Pugh, B. F. Nucleosome positioning and gene regulation: advances through genomics. Nat. Rev. Genet. 10, 161-172 (2009).
126. Kaplan, N. et al. The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458, 362-366 (2009).
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).
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).
129. Li, W. et al. Alternative cleavage and polyadenylation in spermatogenesis connects chromatin regulation with post-transcriptional control. BMC Biol. 14, 6 (2016).
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).
131. Eckmann, C. R., Rammelt, C. & Wahle, E. Control of poly(A) tail length. Wiley Interdiscip. Rev. RNA 2, 348-361 (2011).
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).
133. Mendez, R. & Richter, J. D. Translational control by CPEB: a means to the end. Nat. Rev. Mol. Cell Biol. 2, 521-529 (2001).
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).
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).
136. Wang, K. C. & Chang, H. Y. Molecular mechanisms of long noncoding RNAs. Mol. Cell 43, 904-914 (2011).
137. Naganuma, T. et al. Alternative 3'-end processing of long noncoding RNA initiates construction of nuclear paraspeckles. EMBO J. 31, 4020-4034 (2012).
138. Higgs, D. R. et al. Thalassaemia caused by a polyadenylation signal mutation. Nature 306, 398-400 (1983).
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).
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).
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).
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).
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).
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).
145. Cheng, Y., Miura, R. M. & Tian, B. Prediction of mRNA polyadenylation sites by support vector machine. Bioinformatics 22, 2320-2325 (2006).
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).
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).
148. Shi, Y. et al. Molecular architecture of the human pre-mRNA 3' processing complex. Mol. Cell 33, 365-376 (2009).
149. Chan, S. L. et al. CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3' processing. Genes Dev. 28, 2370-2380 (2014).
150. Schonemann, L. et al. Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33. Genes Dev. 28, 2381-2393 (2014).
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).
152. Takagaki, Y. & Manley, J. L. RNA recognition by the human polyadenylation factor CstF. Mol. Cell. Biol. 17, 3907-3914 (1997).
153. Chen, F. & Wilusz, J. Auxiliary downstream elements are required for efficient polyadenylation of mammalian pre-mRNAs. Nucleic Acids Res. 26, 2891-2898 (1998).
154. Mandel, C. R. et al. Polyadenylation factor CPSF-73 is the pre-mRNA 3'-end-processing endonuclease. Nature 444, 953-956 (2006).
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).
156. Yang, Q., Gilmartin, G. M. & Doublie, 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).
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).
158. Zhang, H., Lee, J. Y. & Tian, B. Biased alternative polyadenylation in human tissues. Genome Biol. 6, R100 (2005).
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).
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).
161. Liu, D. et al. Systematic variation in mRNA 3'-processing signals during mouse spermatogenesis. Nucleic Acids Res. 35, 234-246 (2007).
162. Smibert, P. et al. Global patterns of tissue-specific alternative polyadenylation in Drosophila. Cell Rep. 1, 277-289 (2012).
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).
164. Shepard, P. J. et al. Complex and dynamic landscape of RNA polyadenylation revealed by PAS-Seq. RNA 17, 761-772 (2011).
165. Dai, W. et al. A post-transcriptional mechanism pacing expression of neural genes with precursor cell differentiation status. Nat. Commun. 6, 7576 (2015).
166. Dass, B. et al. Loss of polyadenylation protein CstF-64 causes spermatogenic defects and male infertility. Proc. Natl Acad. Sci. USA 104, 20374-20379 (2007).
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).
168. Soumillon, M. et al. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. Cell Rep. 3, 2179-2190 (2013).
169. Zhang, P. et al. MIWI and piRNA-mediated cleavage of messenger RNAs in mouse testes. Cell Res. 25, 193-207 (2015).
170. Goh, W. S. et al. piRNA-directed cleavage of meiotic transcripts regulates spermatogenesis. Genes Dev. 29, 1032-1044 (2015).
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).
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).
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).
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).
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).
176. Morris, A. R. et al. Alternative cleavage and polyadenylation during colorectal cancer development. Clin. Cancer Res. 18, 5256-5266 (2012).
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).
178. Chang, J. W. et al. mRNA 3'-UTR shortening is a molecular signature of mTORC1 activation. Nat. Commun. 6, 7218 (2015).