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RNA modifications and structures cooperate to guide RNA–protein interactions

Abstract

An emerging body of evidence indicates that post-transcriptional gene regulation relies not only on the sequence of mRNAs but also on their folding into intricate secondary structures and on the chemical modifications of the RNA bases. These features, which are highly dynamic and interdependent, exert direct control over the transcriptome and thereby influence many aspects of cell function. Here, we consider how the coupling of RNA modifications and structures shapes RNA–protein interactions at different steps of the gene expression process.

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Figure 1: RNA modifications and their writers, erasers and readers.
Figure 2: Biological functions of mRNA modifications.
Figure 3: Stress induces N6-methyladenosine-dependent translation.
Figure 4: The effect of RNA structures on mRNA modification and gene expression.
Figure 5: The dynamics of mRNA modification stoichiometries.

References

  1. 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).

    CAS  Article  PubMed  Google Scholar 

  2. Huang, Y., Gattoni, R., Stevenin, J. & Steitz, J. A. SR splicing factors serve as adapter proteins for TAP-dependent mRNA export. Mol. Cell 11, 837–843 (2003).

    CAS  Article  PubMed  Google Scholar 

  3. 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 

  4. Ji, X. et al. SR proteins collaborate with 7SK and promoter-associated nascent RNA to release paused polymerase. Cell 153, 855–868 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Singh, G. et al. The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell 151, 750–764 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Hafner, M. et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141, 129–141 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Konig, J. et al. iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat. Struct. Mol. Biol. 17, 909–915 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Taliaferro, J. M. et al. RNA sequence context effects measured in vitro predict in vivo protein binding and regulation. Mol. Cell 64, 294–306 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Gilbert, W. V., Bell, T. A. & Schaening, C. Messenger RNA modifications: form, distribution, and function. Science 352, 1408–1412 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Lu, Z. et al. RNA duplex map in living cells reveals higher-order transcriptome structure. Cell 165, 1267–1279 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Spitale, R. C. et al. Structural imprints in vivo decode RNA regulatory mechanisms. Nature 519, 486–490 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Sugimoto, Y. et al. hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1. Nature 519, 491–494 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Nishikura, K. A-To-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 17, 83–96 (2016).

    CAS  Article  PubMed  Google Scholar 

  14. Blanc, V. & Davidson, N. O. APOBEC-1-mediated RNA editing. Wiley Interdiscip. Rev. Syst. Biol. Med. 2, 594–602 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Cantara, W. A. et al. The RNA Modification Database, RNAMDB: 2011 update. Nucleic Acids Res. 39, D195–D201 (2011).

    CAS  Article  PubMed  Google Scholar 

  16. El Yacoubi, B., Bailly, M. & de Crecy-Lagard, V. Biosynthesis and function of posttranscriptional modifications of transfer RNAs. Annu. Rev. Genet. 46, 69–95 (2012).

    CAS  Article  PubMed  Google Scholar 

  17. Karijolich, J., Kantartzis, A. & Yu, Y. T. RNA modifications: a mechanism that modulates gene expression. Methods Mol. Biol. 629, 1–19 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Barash, Y. et al. Deciphering the splicing code. Nature 465, 53–59 (2010).

    CAS  Article  PubMed  Google Scholar 

  19. Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012).

    CAS  Article  PubMed  Google Scholar 

  20. Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Schwartz, S. et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep. 8, 284–296 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Agarwala, S. D., Blitzblau, H. G., Hochwagen, A. & Fink, G. R. RNA methylation by the MIS complex regulates a cell fate decision in yeast. PLoS Genet. 8, e1002732 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Horiuchi, K. et al. Identification of Wilms' tumor 1-associating protein complex and its role in alternative splicing and the cell cycle. J. Biol. Chem. 288, 33292–33302 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Liu, J. et al. A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 10, 93–95 (2014).

    CAS  Article  PubMed  Google Scholar 

  25. Patil, D. P. et al. m6A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537, 369–373 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Ping, X. L. et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 24, 177–189 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Zhong, S. et al. MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor. Plant Cell 20, 1278–1288 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Jia, G. et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 7, 885–887 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Zhao, X. et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 24, 1403–1419 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Wang, Y. et al. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat. Cell Biol. 16, 191–198 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Zheng, G. et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18–29 (2013).

    CAS  Article  PubMed  Google Scholar 

  33. Zhong, X. Y., Ding, J. H., Adams, J. A., Ghosh, G. & Fu, X. D. Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones. Genes Dev. 23, 482–495 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Zhong, X. Y., Wang, P., Han, J., Rosenfeld, M. G. & Fu, X. D. SR proteins in vertical integration of gene expression from transcription to RNA processing to translation. Mol. Cell 35, 1–10 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Xiao, W. et al. Nuclear m6A reader YTHDC1 regulates mRNA splicing. Mol. Cell 61, 507–519 (2016).

    CAS  Article  PubMed  Google Scholar 

  36. Haussmann, I.U. et al. m6A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature 540, 301–304 (2016).

    CAS  Article  PubMed  Google Scholar 

  37. Lence, T. et al. m6A modulates neuronal functions and sex determination in Drosophila. Nature 540, 242–247 (2016).

    CAS  Article  PubMed  Google Scholar 

  38. Alarcon, C. R. et al. HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events. Cell 162, 1299–1308 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Carlile, T. M. et al. Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature 515, 143–146 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Li, X. et al. Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nat. Chem. Biol. 11, 592–597 (2015).

    CAS  Article  PubMed  Google Scholar 

  41. Lovejoy, A. F., Riordan, D. P. & Brown, P. O. Transcriptome-wide mapping of pseudouridines: pseudouridine synthases modify specific mRNAs in S. cerevisiae. PLoS ONE 9, e110799 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schwartz, S. et al. Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell 159, 148–162 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Sommer, S., Lavi, U. & Darnell, J. E. Jr. The absolute frequency of labeled N-6-methyladenosine in HeLa cell messenger RNA decreases with label time. J. Mol. Biol. 124, 487–499 (1978).

    CAS  Article  PubMed  Google Scholar 

  44. Batista, P. J. et al. m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Geula, S. et al. Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347, 1002–1006 (2015).

    CAS  Article  PubMed  Google Scholar 

  46. Du, H. et al. YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex. Nat. Commun. 7, 12626 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Wang, X. et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117–120 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Sheth, U. & Parker, R. Decapping and decay of messenger RNA occur in cytoplasmic processing bodies. Science 300, 805–808 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Kennedy, E. M. et al. Posttranscriptional m6A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe 19, 675–685 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Chen, T. et al. m6A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. Cell Stem Cell 16, 289–301 (2015).

    CAS  Article  PubMed  Google Scholar 

  51. Alarcon, C. R., Lee, H., Goodarzi, H., Halberg, N. & Tavazoie, S. F. N6-methyladenosine marks primary microRNAs for processing. Nature 519, 482–485 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Squires, J. E. et al. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 40, 5023–5033 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Mauer, J. et al. Reversible methylation of m6Am in the 5′ cap controls mRNA stability. Nature http://dx.doi.org/10.1038/nature21022 (2016).

  54. Merrick, W. C. Cap-dependent and cap-independent translation in eukaryotic systems. Gene 332, 1–11 (2004).

    CAS  Article  PubMed  Google Scholar 

  55. Wang, X. et al. N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388–1399 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Tirumuru, N. et al. N6-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. Elife 5 e15528 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Meyer, K. D. et al. 5′ UTR m6A promotes cap-independent translation. Cell 163, 999–1010 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Zhou, J. et al. Dynamic m6A mRNA methylation directs translational control of heat shock response. Nature 526, 591–594 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Feigenblum, D. & Schneider, R. J. Cap-binding protein (eukaryotic initiation factor 4E) and 4E-inactivating protein BP-1 independently regulate cap-dependent translation. Mol. Cell. Biol. 16, 5450–5457 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Tang, H. et al. NSun2 delays replicative senescence by repressing p27KIP1 translation and elevating CDK1 translation. Aging (Albany NY) 7, 1143–1158 (2015).

    CAS  Article  Google Scholar 

  61. Xing, J. et al. NSun2 promotes cell growth via elevating cyclin-dependent kinase 1 translation. Mol. Cell. Biol. 35, 4043–4052 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Fu, L. et al. Tet-mediated formation of 5-hydroxymethylcytosine in RNA. J. Am. Chem. Soc. 136, 11582–11585 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. Delatte, B. et al. RNA biochemistry. Transcriptome-wide distribution and function of RNA hydroxymethylcytosine. Science 351, 282–285 (2016).

    CAS  Article  PubMed  Google Scholar 

  64. Dominissini, D. et al. The dynamic N1-methyladenosine methylome in eukaryotic messenger RNA. Nature 530, 441–446 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Li, X. et al. Transcriptome-wide mapping reveals reversible and dynamic N1-methyladenosine methylome. Nat. Chem. Biol. 12, 311–316 (2016).

    CAS  Article  PubMed  Google Scholar 

  66. Karijolich, J., Yi, C. & Yu, Y. T. Transcriptome-wide dynamics of RNA pseudouridylation. Nat. Rev. Mol. Cell Biol. 16, 581–585 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Wan, Y., Kertesz, M., Spitale, R. C., Segal, E. & Chang, H. Y. Understanding the transcriptome through RNA structure. Nat. Rev. Genet. 12, 641–655 (2011).

    CAS  Article  PubMed  Google Scholar 

  68. Dethoff, E. A., Chugh, J., Mustoe, A. M. & Al-Hashimi, H. M. Functional complexity and regulation through RNA dynamics. Nature 482, 322–330 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. Cech, T. R. & Steitz, J. A. The noncoding RNA revolution — trashing old rules to forge new ones. Cell 157, 77–94 (2014).

    CAS  Article  PubMed  Google Scholar 

  70. Sharp, P. A. The centrality of RNA. Cell 136, 577–580 (2009).

    CAS  Article  PubMed  Google Scholar 

  71. Smith, D. J., Query, C. C. & Konarska, M. M. “Nought may endure but mutability”: spliceosome dynamics and the regulation of splicing. Mol. Cell 30, 657–666 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Ding, Y. et al. In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features. Nature 505, 696–700 (2014).

    CAS  Article  PubMed  Google Scholar 

  73. Rouskin, S., Zubradt, M., Washietl, S., Kellis, M. & Weissman, J. S. Genome-wide probing of RNA structure reveals active unfolding of mRNA structures in vivo. Nature 505, 701–705 (2014).

    CAS  Article  PubMed  Google Scholar 

  74. Liu, S. R., Hu, C. G. & Zhang, J. Z. Regulatory effects of cotranscriptional RNA structure formation and transitions. Wiley Interdiscip. Rev. RNA 7, 562–574 (2016).

    CAS  Article  PubMed  Google Scholar 

  75. Zhang, J. & Landick, R. A. Two-way street: regulatory interplay between RNA polymerase and nascent RNA structure. Trends Biochem. Sci. 41, 293–310 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Pan, T. & Sosnick, T. RNA folding during transcription. Annu. Rev. Biophys. Biomol. Struct. 35, 161–175 (2006).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. Jin, Y., Yang, Y. & Zhang, P. New insights into RNA secondary structure in the alternative splicing of pre-mRNAs. RNA Biol. 8, 450–457 (2011).

    CAS  Article  PubMed  Google Scholar 

  80. Wan, Y. et al. Landscape and variation of RNA secondary structure across the human transcriptome. Nature 505, 706–709 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Lovci, M. T. et al. Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges. Nat. Struct. Mol. Biol. 20, 1434–1442 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. Aw, J. G. et al. In vivo mapping of eukaryotic RNA interactomes reveals principles of higher-order organization and regulation. Mol. Cell 62, 603–617 (2016).

    CAS  Article  PubMed  Google Scholar 

  83. Sharma, E., Sterne-Weiler, T., O'Hanlon, D. & Blencowe, B. J. Global mapping of human RNA–RNA interactions. Mol. Cell 62, 618–626 (2016).

    CAS  Article  PubMed  Google Scholar 

  84. Liu, N. et al. N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 518, 560–564 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. McCloskey, A., Taniguchi, I., Shinmyozu, K. & Ohno, M. hnRNP C tetramer measures RNA length to classify RNA polymerase II transcripts for export. Science 335, 1643–1646 (2012).

    CAS  Article  PubMed  Google Scholar 

  86. Zarnack, K. et al. Direct competition between hnRNP C and U2AF65 protects the transcriptome from the exonization of Alu elements. Cell 152, 453–466 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. Kertesz, M. et al. Genome-wide measurement of RNA secondary structure in yeast. Nature 467, 103–107 (2010).

    CAS  Article  PubMed  Google Scholar 

  88. Wan, Y. et al. Genome-wide measurement of RNA folding energies. Mol. Cell 48, 169–181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bugaut, A. & Balasubramanian, S. 5′-UTR RNA G-quadruplexes: translation regulation and targeting. Nucleic Acids Res. 40, 4727–4741 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Guo, J. U. & Bartel, D. P. RNA G-quadruplexes are globally unfolded in eukaryotic cells and depleted in bacteria. Science 353 (2016).

  91. Millevoi, S., Moine, H. & Vagner, S. G-Quadruplexes in RNA biology. Wiley Interdiscip. Rev. RNA 3, 495–507 (2012).

    CAS  Article  PubMed  Google Scholar 

  92. Wolfe, A. L. et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513, 65–70 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. Kenny, P. J. et al. MOV10 and FMRP regulate AGO2 association with microRNA recognition elements. Cell Rep. 9, 1729–1741 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Houseley, J., LaCava, J. & Tollervey, D. RNA-quality control by the exosome. Nat. Rev. Mol. Cell Biol. 7, 529–539 (2006).

    CAS  Article  PubMed  Google Scholar 

  95. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. Moqtaderi, Z., Geisberg, J. V. & Struhl, K. Secondary structures involving the poly(A) tail and other 3′ sequences are major determinants of mRNA isoform stability in yeast. Microb. Cell 1, 137–139 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. Yang, L., Duff, M. O., Graveley, B. R., Carmichael, G. G. & Chen, L. L. Genomewide characterization of non-polyadenylated RNAs. Genome Biol. 12, R16 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. Conrad, N. K., Mili, S., Marshall, E. L., Shu, M. D. & Steitz, J. A. Identification of a rapid mammalian deadenylation-dependent decay pathway and its inhibition by a viral RNA element. Mol. Cell 24, 943–953 (2006).

    CAS  Article  PubMed  Google Scholar 

  101. Conrad, N. K., Shu, M. D., Uyhazi, K. E. & Steitz, J. A. Mutational analysis of a viral RNA element that counteracts rapid RNA decay by interaction with the polyadenylate tail. Proc. Natl Acad. Sci. USA 104, 10412–10417 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. Conrad, N. K. & Steitz, J. A. A. Kaposi's sarcoma virus RNA element that increases the nuclear abundance of intronless transcripts. EMBO J. 24, 1831–1841 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Brown, J. A., Valenstein, M. L., Yario, T. A., Tycowski, K. T. & Steitz, J. A. Formation of triple-helical structures by the 3′-end sequences of MALAT1 and MENβ noncoding RNAs. Proc. Natl Acad. Sci. USA 109, 19202–19207 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. Wilusz, J. E. et al. A triple helix stabilizes the 3′ ends of long noncoding RNAs that lack poly(A) tails. Genes Dev. 26, 2392–2407 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. Sunwoo, H. et al. MEN ε/β nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles. Genome Res. 19, 347–359 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. Wilusz, J. E., Freier, S. M. & Spector, D. L. 3′ end processing of a long nuclear-retained noncoding RNA yields a tRNA-like cytoplasmic RNA. Cell 135, 919–932 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. Kierzek, E. & Kierzek, R. The thermodynamic stability of RNA duplexes and hairpins containing N6-alkyladenosines and 2-methylthio-N6-alkyladenosines. Nucleic Acids Res. 31, 4472–4480 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. Roost, C. et al. Structure and thermodynamics of N6-methyladenosine in RNA: a spring-loaded base modification. J. Am. Chem. Soc. 137, 2107–2115 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. Heraud-Farlow, J. E. & Kiebler, M. A. The multifunctional Staufen proteins: conserved roles from neurogenesis to synaptic plasticity. Trends Neurosci. 37, 470–479 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. Csepany, T., Lin, A., Baldick, C. J. Jr & Beemon, K. Sequence specificity of mRNA N6-adenosine methyltransferase. J. Biol. Chem. 265, 20117–20122 (1990).

    CAS  PubMed  Google Scholar 

  112. Horowitz, S., Horowitz, A., Nilsen, T. W., Munns, T. W. & Rottman, F. M. Mapping of N6-methyladenosine residues in bovine prolactin mRNA. Proc. Natl Acad. Sci. USA 81, 5667–5671 (1984).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. Liu, N. et al. Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA. RNA 19, 1848–1856 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

A.K. is supported by grants from the US National Institutes of Health (R01HL126845), the March of Dimes (5-FY14-112) and the Center for Advanced Study at the University of Illinois, Chicago, USA. T.P. is supported by the US National Institutes of Health (R01GM113194). The authors apologize to those whose work could not be cited owing to space restraints.

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Lewis, C., Pan, T. & Kalsotra, A. RNA modifications and structures cooperate to guide RNA–protein interactions. Nat Rev Mol Cell Biol 18, 202–210 (2017). https://doi.org/10.1038/nrm.2016.163

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