Advertisement

Targeting RNA G-Quadruplexes for Potential Therapeutic Applications

  • Satyaprakash Pandey
  • Prachi Agarwala
  • Souvik MaitiEmail author
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 27)

Abstract

RNA G-quadruplexes are non-canonical structures formed in G-rich regions of transcriptome. Considerable research points towards the potential role for these dynamic structures in various genes involved in multiple pathways. The ability of these structures to influence important biological processes has been demonstrated in few selected important genes and more recently in a global manner across the transcriptome. RNA G-quadruplexes are implicated in fundamental processes such as translational regulation, alternative splicing, mRNA transport and telomere homeostasis to name a few. The involvement of these structures in key biological processes makes them attractive targets for therapeutic interventions. Here we discuss the structural features of RNA G-quadruplex that make it more monomorphic to develop ligands unlike the polymorphic DNA G-quadruplexes. Furthermore, the role of RNA G-quadruplexes in important genes involved in diseases and disorders such as neurodegeneration, cancer and viral infections has been highlighted. A summary of ligands and their established roles in targeting RNA G-quadruplex structures has been discussed in context of important processes. Moreover, we highlight the need to develop ligands that are highly specific in targeting RNA G-quadruplexes, a new target to restore homeostasis in dysregulated conditions.

Keywords

Cancer Homesostasis Ligands Neurodegeneration RNA G-quadruplexes Viral infections 

Notes

Acknowledgements

The authors acknowledge Manoj Teltumbade for help with chemical structures and valuable inputs. This work was financially supported by the BSC0123 project (Project: Genome Dynamics in Cellular Organization, Differentiation and Enantiostasis) from the Council of Scientific and Industrial Research (CSIR), Government of India.

References

  1. 1.
    Crick F (1970) Central dogma of molecular biology. Nature 227:561–563CrossRefGoogle Scholar
  2. 2.
    Hangauer MJ, Vaughn IW, McManus MT (2013) Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs. PLoS Genet 9:e1003569CrossRefGoogle Scholar
  3. 3.
    Wan Y, Kertesz M, Spitale RC, Segal E, Chang HY (2011) Understanding the transcriptome through RNA structure. Nat Rev Genet 12:641–655CrossRefGoogle Scholar
  4. 4.
    Doudna JA, Cech TR (2002) The chemical repertoire of natural ribozymes. Nature 418:222–228CrossRefGoogle Scholar
  5. 5.
    Mandal M, Breaker RR (2004) Gene regulation by riboswitches. Nat Rev Mol Cell Biol 5:451–463CrossRefGoogle Scholar
  6. 6.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297CrossRefGoogle Scholar
  7. 7.
    Carter AP, Clemons WM, Brodersen DE, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V (2000) Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature 407:340–348CrossRefGoogle Scholar
  8. 8.
    Brodersen DE, Clemons WM Jr, Carter AP, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V (2000) The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell 103:1143–1154CrossRefGoogle Scholar
  9. 9.
    Regulski EE, Breaker RR (2008) In-line probing analysis of riboswitches. Methods Mol Biol 419:53–67CrossRefGoogle Scholar
  10. 10.
    Tijerina P, Mohr S, Russell R (2007) DMS footprinting of structured RNAs and RNA-protein complexes. Nat Protoc 2:2608–2623CrossRefGoogle Scholar
  11. 11.
    Kolupaeva VG, Pestova TV, Hellen CU (2000) An enzymatic footprinting analysis of the interaction of 40S ribosomal subunits with the internal ribosomal entry site of hepatitis C virus. J Virol 74:6242–6250CrossRefGoogle Scholar
  12. 12.
    Kertesz M, Wan Y, Mazor E, Rinn JL, Nutter RC, Chang HY, Segal E (2010) Genome-wide measurement of RNA secondary structure in yeast. Nature 467:103–107CrossRefGoogle Scholar
  13. 13.
    Lucks JB, Mortimer SA, Trapnell C, Luo S, Aviran S, Schroth GP, Pachter L, Doudna JA, Arkin AP (2011) Multiplexed RNA structure characterization with selective 2'-hydroxyl acylation analyzed by primer extension sequencing (SHAPE-Seq). Proc Natl Acad Sci U S A 108:11063–11068CrossRefGoogle Scholar
  14. 14.
    Puglisi JD, Chen L, Frankel AD, Williamson JR (1993) Role of RNA structure in arginine recognition of TAR RNA. Proc Natl Acad Sci U S A 90:3680–3684CrossRefGoogle Scholar
  15. 15.
    Laughlan G, Murchie AI, Norman DG, Moore MH, Moody PC, Lilley DM, Luisi B (1994) The high-resolution crystal structure of a parallel-stranded guanine tetraplex. Science 265:520–524CrossRefGoogle Scholar
  16. 16.
    Phillips K, Dauter Z, Murchie AI, Lilley DM, Luisi B (1997) The crystal structure of a parallel-stranded guanine tetraplex at 0.95 A resolution. J Mol Biol 273:171–182CrossRefGoogle Scholar
  17. 17.
    Mortimer SA, Trapnell C, Aviran S, Pachter L, Lucks JB (2012) SHAPE-Seq: high-throughput RNA structure analysis. Curr Protoc Chem Biol 4:275–297Google Scholar
  18. 18.
    Wan Y, Qu K, Ouyang Z, Kertesz M, Li J, Tibshirani R, Makino DL, Nutter RC, Segal E, Chang HY (2012) Genome-wide measurement of RNA folding energies. Mol Cell 48:169–181CrossRefGoogle Scholar
  19. 19.
    Werstuck G, Green MR (1998) Controlling gene expression in living cells through small molecule-RNA interactions. Science 282:296–298CrossRefGoogle Scholar
  20. 20.
    Weeks KM, Crothers DM (1991) RNA recognition by Tat-derived peptides: interaction in the major groove? Cell 66:577–588CrossRefGoogle Scholar
  21. 21.
    Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S, Oostra B, Bagni C (2003) The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 112:317–327CrossRefGoogle Scholar
  22. 22.
    Kedde M, Strasser MJ, Boldajipour B, Oude Vrielink JA, Slanchev K, le Sage C, Nagel R, Voorhoeve PM, van Duijse J, Orom UA, Lund AH, Perrakis A, Raz E, Agami R (2007) RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell 131:1273–1286CrossRefGoogle Scholar
  23. 23.
    Martianov I, Ramadass A, Serra Barros A, Chow N, Akoulitchev A (2007) Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 445:666–670CrossRefGoogle Scholar
  24. 24.
    Jain A, Wang G, Vasquez KM (2008) DNA triple helices: biological consequences and therapeutic potential. Biochimie 90:1117–1130CrossRefGoogle Scholar
  25. 25.
    Buske FA, Mattick JS, Bailey TL (2011) Potential in vivo roles of nucleic acid triple-helices. RNA Biol 8:427–439CrossRefGoogle Scholar
  26. 26.
    Mondal T, Subhash S, Vaid R, Enroth S, Uday S, Reinius B, Mitra S, Mohammed A, James AR, Hoberg E, Moustakas A, Gyllensten U, Jones SJ, Gustafsson CM, Sims AH, Westerlund F, Gorab E, Kanduri C (2015) MEG3 long noncoding RNA regulates the TGF-beta pathway genes through formation of RNA-DNA triplex structures. Nat Commun 6:7743CrossRefGoogle Scholar
  27. 27.
    Gellert M, Lipsett MN, Davies DR (1962) Helix formation by guanylic acid. Proc Natl Acad Sci U S A 48:2013–2018CrossRefGoogle Scholar
  28. 28.
    Smith FW, Feigon J (1992) Quadruplex structure of Oxytricha telomeric DNA oligonucleotides. Nature 356:164–168CrossRefGoogle Scholar
  29. 29.
    Hardin CC, Watson T, Corregan M, Bailey C (1992) Cation-dependent transition between the quadruplex and Watson-Crick hairpin forms of d(CGCG3GCG). Biochemistry 31:833–841CrossRefGoogle Scholar
  30. 30.
    Burge S, Parkinson GN, Hazel P, Todd AK, Neidle S (2006) Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res 34:5402–5415CrossRefGoogle Scholar
  31. 31.
    Eddy J, Maizels N (2006) Gene function correlates with potential for G4 DNA formation in the human genome. Nucleic Acids Res 34:3887–3896CrossRefGoogle Scholar
  32. 32.
    Gomez D, Lemarteleur T, Lacroix L, Mailliet P, Mergny JL, Riou JF (2004) Telomerase downregulation induced by the G-quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing. Nucleic Acids Res 32:371–379CrossRefGoogle Scholar
  33. 33.
    Monchaud D, Teulade-Fichou MP (2008) A hitchhiker’s guide to G-quadruplex ligands. Org Biomol Chem 6:627–636CrossRefGoogle Scholar
  34. 34.
    Kim J, Cheong C, Moore PB (1991) Tetramerization of an RNA oligonucleotide containing a GGGG sequence. Nature 351:331–332CrossRefGoogle Scholar
  35. 35.
    Christiansen J, Kofod M, Nielsen FC (1994) A guanosine quadruplex and two stable hairpins flank a major cleavage site in insulin-like growth factor II mRNA. Nucleic Acids Res 22:5709–5716CrossRefGoogle Scholar
  36. 36.
    Patel DJ, Phan AT, Kuryavyi V (2007) Human telomere, oncogenic promoter and 5'-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics. Nucleic Acids Res 35:7429–7455CrossRefGoogle Scholar
  37. 37.
    Kumari S, Bugaut A, Huppert JL, Balasubramanian S (2007) An RNA G-quadruplex in the 5' UTR of the NRAS proto-oncogene modulates translation. Nat Chem Biol 3:218–221CrossRefGoogle Scholar
  38. 38.
    Arora A, Dutkiewicz M, Scaria V, Hariharan M, Maiti S, Kurreck J (2008) Inhibition of translation in living eukaryotic cells by an RNA G-quadruplex motif. RNA 14:1290–1296CrossRefGoogle Scholar
  39. 39.
    Morris MJ, Basu S (2009) An unusually stable G-quadruplex within the 5'-UTR of the MT3 matrix metalloproteinase mRNA represses translation in eukaryotic cells. Biochemistry 48:5313–5319CrossRefGoogle Scholar
  40. 40.
    Jayaraj GG, Pandey S, Scaria V, Maiti S (2012) Potential G-quadruplexes in the human long non-coding transcriptome. RNA Biol 9:81–86CrossRefGoogle Scholar
  41. 41.
    Arora A, Maiti S (2009) Differential biophysical behavior of human telomeric RNA and DNA quadruplex. J Phys Chem B 113:10515–10520CrossRefGoogle Scholar
  42. 42.
    Zhang DH, Fujimoto T, Saxena S, Yu HQ, Miyoshi D, Sugimoto N (2010) Monomorphic RNA G-quadruplex and polymorphic DNA G-quadruplex structures responding to cellular environmental factors. Biochemistry 49:4554–4563CrossRefGoogle Scholar
  43. 43.
    Huppert JL, Bugaut A, Kumari S, Balasubramanian S (2008) G-quadruplexes: the beginning and end of UTRs. Nucleic Acids Res 36:6260–6268CrossRefGoogle Scholar
  44. 44.
    Gros J, Guedin A, Mergny JL, Lacroix L (2008) G-Quadruplex formation interferes with P1 helix formation in the RNA component of telomerase hTERC. Chembiochem 9:2075–2079CrossRefGoogle Scholar
  45. 45.
    Marcel V, Tran PL, Sagne C, Martel-Planche G, Vaslin L, Teulade-Fichou MP, Hall J, Mergny JL, Hainaut P, Van Dyck E (2011) G-quadruplex structures in TP53 intron 3: role in alternative splicing and in production of p53 mRNA isoforms. Carcinogenesis 32:271–278CrossRefGoogle Scholar
  46. 46.
    Subramanian M, Rage F, Tabet R, Flatter E, Mandel JL, Moine H (2011) G-quadruplex RNA structure as a signal for neurite mRNA targeting. EMBO Rep 12:697–704CrossRefGoogle Scholar
  47. 47.
    Biffi G, Di Antonio M, Tannahill D, Balasubramanian S (2014) Visualization and selective chemical targeting of RNA G-quadruplex structures in the cytoplasm of human cells. Nat Chem 6:75–80CrossRefGoogle Scholar
  48. 48.
    Hagihara M, Yoneda K, Yabuuchi H, Okuno Y, Nakatani K (2010) A reverse transcriptase stop assay revealed diverse quadruplex formations in UTRs in mRNA. Bioorg Med Chem Lett 20:2350–2353CrossRefGoogle Scholar
  49. 49.
    Kwok CK, Marsico G, Sahakyan AB, Chambers VS, Balasubramanian S (2016) rG4-seq reveals widespread formation of G-quadruplex structures in the human transcriptome. Nat Methods 13:841–844CrossRefGoogle Scholar
  50. 50.
    Guo JU, Bartel DP (2016) RNA G-quadruplexes are globally unfolded in eukaryotic cells and depleted in bacteria. Science 353Google Scholar
  51. 51.
    Morris MJ, Negishi Y, Pazsint C, Schonhoft JD, Basu S (2010) An RNA G-quadruplex is essential for cap-independent translation initiation in human VEGF IRES. J Am Chem Soc 132:17831–17839CrossRefGoogle Scholar
  52. 52.
    Agarwala P, Pandey S, Mapa K, Maiti S (2013) The G-quadruplex augments translation in the 5' untranslated region of transforming growth factor beta2. Biochemistry 52:1528–1538CrossRefGoogle Scholar
  53. 53.
    Hazel P, Huppert J, Balasubramanian S, Neidle S (2004) Loop-length-dependent folding of G-quadruplexes. J Am Chem Soc 126:16405–16415CrossRefGoogle Scholar
  54. 54.
    Bugaut A, Balasubramanian S (2008) A sequence-independent study of the influence of short loop lengths on the stability and topology of intramolecular DNA G-quadruplexes. Biochemistry 47:689–697CrossRefGoogle Scholar
  55. 55.
    Guedin A, Gros J, Alberti P, Mergny JL (2010) How long is too long? Effects of loop size on G-quadruplex stability. Nucleic Acids Res 38:7858–7868CrossRefGoogle Scholar
  56. 56.
    Zhang AY, Bugaut A, Balasubramanian S (2011) A sequence-independent analysis of the loop length dependence of intramolecular RNA G-quadruplex stability and topology. Biochemistry 50:7251–7258CrossRefGoogle Scholar
  57. 57.
    Pandey S, Agarwala P, Maiti S (2013) Effect of loops and G-quartets on the stability of RNA G-quadruplexes. J Phys Chem B 117:6896–6905CrossRefGoogle Scholar
  58. 58.
    Jodoin R, Bauer L, Garant JM, Mahdi Laaref A, Phaneuf F, Perreault JP (2014) The folding of 5'-UTR human G-quadruplexes possessing a long central loop. RNA 20:1129–1141CrossRefGoogle Scholar
  59. 59.
    Joachimi A, Benz A, Hartig JS (2009) A comparison of DNA and RNA quadruplex structures and stabilities. Bioorg Med Chem 17:6811–6815CrossRefGoogle Scholar
  60. 60.
    Tang CF, Shafer RH (2006) Engineering the quadruplex fold: nucleoside conformation determines both folding topology and molecularity in guanine quadruplexes. J Am Chem Soc 128:5966–5973CrossRefGoogle Scholar
  61. 61.
    Liu H, Kanagawa M, Matsugami A, Tanaka Y, Katahira M, Uesugi S (2000) NMR study of a novel RNA quadruplex structure. Nucleic Acids Symp Ser:65–66Google Scholar
  62. 62.
    Liu H, Kugimiya A, Sakurai T, Katahira M, Uesugi S (2002) A comparison of the properties and the solution structure for RNA and DNA quadruplexes which contain two GGAGG sequences joined with a tetranucleotide linker. Nucleosides Nucleotides Nucleic Acids 21:785–801CrossRefGoogle Scholar
  63. 63.
    Greider CW, Blackburn EH (1989) A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337:331–337CrossRefGoogle Scholar
  64. 64.
    Shay JW, Wright WE (2011) Role of telomeres and telomerase in cancer. Semin Cancer Biol 21:349–353CrossRefGoogle Scholar
  65. 65.
    Wang Q, Liu JQ, Chen Z, Zheng KW, Chen CY, Hao YH, Tan Z (2011) G-quadruplex formation at the 3' end of telomere DNA inhibits its extension by telomerase, polymerase and unwinding by helicase. Nucleic Acids Res 39:6229–6237CrossRefGoogle Scholar
  66. 66.
    Parkinson GN, Lee MP, Neidle S (2002) Crystal structure of parallel quadruplexes from human telomeric DNA. Nature 417:876–880CrossRefGoogle Scholar
  67. 67.
    Collie GW, Haider SM, Neidle S, Parkinson GN (2010) A crystallographic and modelling study of a human telomeric RNA (TERRA) quadruplex. Nucleic Acids Res 38:5569–5580CrossRefGoogle Scholar
  68. 68.
    Xu L, Feng S, Zhou X (2011) Human telomeric G-quadruplexes undergo dynamic conversion in a molecular crowding environment. Chem Commun (Camb) 47:3517–3519CrossRefGoogle Scholar
  69. 69.
    Collie GW, Parkinson GN, Neidle S, Rosu F, De Pauw E, Gabelica V (2010) Electrospray mass spectrometry of telomeric RNA (TERRA) reveals the formation of stable multimeric G-quadruplex structures. J Am Chem Soc 132:9328–9334CrossRefGoogle Scholar
  70. 70.
    Martadinata H, Phan AT (2009) Structure of propeller-type parallel-stranded RNA G-quadruplexes, formed by human telomeric RNA sequences in K+ solution. J Am Chem Soc 131:2570–2578CrossRefGoogle Scholar
  71. 71.
    Sacca B, Lacroix L, Mergny JL (2005) The effect of chemical modifications on the thermal stability of different G-quadruplex-forming oligonucleotides. Nucleic Acids Res 33:1182–1192CrossRefGoogle Scholar
  72. 72.
    Olsen CM, Marky LA (2009) Energetic and hydration contributions of the removal of methyl groups from thymine to form uracil in G-quadruplexes. J Phys Chem B 113:9–11CrossRefGoogle Scholar
  73. 73.
    Ji X, Sun H, Zhou H, Xiang J, Tang Y, Zhao C (2011) Research progress of RNA quadruplex. Nucleic Acid Ther 21:185–200CrossRefGoogle Scholar
  74. 74.
    Agarwal T, Jayaraj G, Pandey SP, Agarwala P, Maiti S (2012) RNA G-quadruplexes: G-quadruplexes with “U” turns. Curr Pharm Des 18:2102–2111CrossRefGoogle Scholar
  75. 75.
    Decorsiere A, Cayrel A, Vagner S, Millevoi S (2011) Essential role for the interaction between hnRNP H/F and a G quadruplex in maintaining p53 pre-mRNA 3'-end processing and function during DNA damage. Genes Dev 25:220–225CrossRefGoogle Scholar
  76. 76.
    Wieland M, Hartig JS (2007) RNA quadruplex-based modulation of gene expression. Chem Biol 14:757–763CrossRefGoogle Scholar
  77. 77.
    Bhattacharyya D, Diamond P, Basu S (2015) An independently folding RNA G-quadruplex domain directly recruits the 40S ribosomal subunit. Biochemistry 54:1879–1885CrossRefGoogle Scholar
  78. 78.
    Bonnal S, Schaeffer C, Creancier L, Clamens S, Moine H, Prats AC, Vagner S (2003) A single internal ribosome entry site containing a G quartet RNA structure drives fibroblast growth factor 2 gene expression at four alternative translation initiation codons. J Biol Chem 278:39330–39336CrossRefGoogle Scholar
  79. 79.
    Halder K, Wieland M, Hartig JS (2009) Predictable suppression of gene expression by 5'-UTR-based RNA quadruplexes. Nucleic Acids Res 37:6811–6817CrossRefGoogle Scholar
  80. 80.
    Shahid R, Bugaut A, Balasubramanian S (2010) The BCL-2 5' untranslated region contains an RNA G-quadruplex-forming motif that modulates protein expression. Biochemistry 49:8300–8306CrossRefGoogle Scholar
  81. 81.
    Endoh T, Kawasaki Y, Sugimoto N (2013) Suppression of gene expression by G-quadruplexes in open reading frames depends on G-quadruplex stability. Angew Chem Int Ed Engl 52:5522–5526CrossRefGoogle Scholar
  82. 82.
    Arora A, Suess B (2011) An RNA G-quadruplex in the 3' UTR of the proto-oncogene PIM1 represses translation. RNA Biol 8:802–805CrossRefGoogle Scholar
  83. 83.
    Maizels N (2015) G4-associated human diseases. EMBO Rep 16:910–922CrossRefGoogle Scholar
  84. 84.
    Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, Nelson DL (1991) Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66:817–822CrossRefGoogle Scholar
  85. 85.
    Coffee B, Keith K, Albizua I, Malone T, Mowrey J, Sherman SL, Warren ST (2009) Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet 85:503–514CrossRefGoogle Scholar
  86. 86.
    Sutcliffe JS, Nelson DL, Zhang F, Pieretti M, Caskey CT, Saxe D, Warren ST (1992) DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet 1:397–400CrossRefGoogle Scholar
  87. 87.
    Feng Y, Gutekunst CA, Eberhart DE, Yi H, Warren ST, Hersch SM (1997) Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. J Neurosci 17:1539–1547Google Scholar
  88. 88.
    Blackwell E, Zhang X, Ceman S (2010) Arginines of the RGG box regulate FMRP association with polyribosomes and mRNA. Hum Mol Genet 19:1314–1323CrossRefGoogle Scholar
  89. 89.
    Brown V, Jin P, Ceman S, Darnell JC, O’Donnell WT, Tenenbaum SA, Jin X, Feng Y, Wilkinson KD, Keene JD, Darnell RB, Warren ST (2001) Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell 107:477–487CrossRefGoogle Scholar
  90. 90.
    Darnell JC, Jensen KB, Jin P, Brown V, Warren ST, Darnell RB (2001) Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell 107:489–499CrossRefGoogle Scholar
  91. 91.
    Lu R, Wang H, Liang Z, Ku L, O’Donnell WT, Li W, Warren ST, Feng Y (2004) The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development. Proc Natl Acad Sci U S A 101:15201–15206CrossRefGoogle Scholar
  92. 92.
    Castets M, Schaeffer C, Bechara E, Schenck A, Khandjian EW, Luche S, Moine H, Rabilloud T, Mandel JL, Bardoni B (2005) FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts. Hum Mol Genet 14:835–844CrossRefGoogle Scholar
  93. 93.
    Khateb S, Weisman-Shomer P, Hershco-Shani I, Ludwig AL, Fry M (2007) The tetraplex (CGG)n destabilizing proteins hnRNP A2 and CBF-A enhance the in vivo translation of fragile X premutation mRNA. Nucleic Acids Res 35:5775–5788CrossRefGoogle Scholar
  94. 94.
    Schaeffer C, Bardoni B, Mandel JL, Ehresmann B, Ehresmann C, Moine H (2001) The fragile X mental retardation protein binds specifically to its mRNA via a purine quartet motif. EMBO J 20:4803–4813CrossRefGoogle Scholar
  95. 95.
    Westmark CJ, Malter JS (2007) FMRP mediates mGluR5-dependent translation of amyloid precursor protein. PLoS Biol 5:e52CrossRefGoogle Scholar
  96. 96.
    Suhl JA, Chopra P, Anderson BR, Bassell GJ, Warren ST (2014) Analysis of FMRP mRNA target datasets reveals highly associated mRNAs mediated by G-quadruplex structures formed via clustered WGGA sequences. Hum Mol Genet 23:5479–5491CrossRefGoogle Scholar
  97. 97.
    Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438CrossRefGoogle Scholar
  98. 98.
    Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268CrossRefGoogle Scholar
  99. 99.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256CrossRefGoogle Scholar
  100. 100.
    Fratta P, Mizielinska S, Nicoll AJ, Zloh M, Fisher EM, Parkinson G, Isaacs AM (2012) C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep 2:1016CrossRefGoogle Scholar
  101. 101.
    Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507:195–200CrossRefGoogle Scholar
  102. 102.
    Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525:129–133CrossRefGoogle Scholar
  103. 103.
    Jovicic A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G, Kramer NJ, Gage FH, Van Den Bosch L, Robberecht W, Gitler AD (2015) Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 18:1226–1229CrossRefGoogle Scholar
  104. 104.
    Zamiri B, Reddy K, Macgregor RB Jr, Pearson CE (2014) TMPyP4 porphyrin distorts RNA G-quadruplex structures of the disease-associated r(GGGGCC)n repeat of the C9orf72 gene and blocks interaction of RNA-binding proteins. J Biol Chem 289:4653–4659CrossRefGoogle Scholar
  105. 105.
    Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J, Yang WY, Fostvedt E, Jansen-West K, Belzil VV, Desaro P, Johnston A, Overstreet K, Oh SY, Todd PK, Berry JD, Cudkowicz ME, Boeve BF, Dickson D, Floeter MK, Traynor BJ, Morelli C, Ratti A, Silani V, Rademakers R, Brown RH, Rothstein JD, Boylan KB, Petrucelli L, Disney MD (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83:1043–1050CrossRefGoogle Scholar
  106. 106.
    Nunan J, Small DH (2000) Regulation of APP cleavage by alpha-, beta- and gamma-secretases. FEBS Lett 483:6–10CrossRefGoogle Scholar
  107. 107.
    Tanzi RE (2005) The synaptic Abeta hypothesis of Alzheimer disease. Nat Neurosci 8:977–979CrossRefGoogle Scholar
  108. 108.
    Weyer SW, Zagrebelsky M, Herrmann U, Hick M, Ganss L, Gobbert J, Gruber M, Altmann C, Korte M, Deller T, Muller UC (2014) Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsalpha expression. Acta Neuropathol Commun 2:36CrossRefGoogle Scholar
  109. 109.
    Crenshaw E, Leung BP, Kwok CK, Sharoni M, Olson K, Sebastian NP, Ansaloni S, Schweitzer-Stenner R, Akins MR, Bevilacqua PC, Saunders AJ (2015) Amyloid precursor protein translation is regulated by a 3'UTR guanine quadruplex. PLoS One 10:e0143160CrossRefGoogle Scholar
  110. 110.
    Lammich S, Kamp F, Wagner J, Nuscher B, Zilow S, Ludwig AK, Willem M, Haass C (2011) Translational repression of the disintegrin and metalloprotease ADAM10 by a stable G-quadruplex secondary structure in its 5'-untranslated region. J Biol Chem 286:45063–45072CrossRefGoogle Scholar
  111. 111.
    Fisette JF, Montagna DR, Mihailescu MR, Wolfe MS (2012) A G-rich element forms a G-quadruplex and regulates BACE1 mRNA alternative splicing. J Neurochem 121:763–773CrossRefGoogle Scholar
  112. 112.
    Kapranov P, Cawley SE, Drenkow J, Bekiranov S, Strausberg RL, Fodor SP, Gingeras TR (2002) Large-scale transcriptional activity in chromosomes 21 and 22. Science 296:916–919CrossRefGoogle Scholar
  113. 113.
    Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–166CrossRefGoogle Scholar
  114. 114.
    Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigo R (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22:1775–1789CrossRefGoogle Scholar
  115. 115.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233CrossRefGoogle Scholar
  116. 116.
    Lujambio A, Lowe SW (2012) The microcosmos of cancer. Nature 482:347–355CrossRefGoogle Scholar
  117. 117.
    Mendell JT, Olson EN (2012) MicroRNAs in stress signaling and human disease. Cell 148:1172–1187CrossRefGoogle Scholar
  118. 118.
    Zampetaki A, Mayr M (2012) MicroRNAs in vascular and metabolic disease. Circ Res 110:508–522CrossRefGoogle Scholar
  119. 119.
    Esau CC (2008) Inhibition of microRNA with antisense oligonucleotides. Methods 44:55–60CrossRefGoogle Scholar
  120. 120.
    Young DD, Connelly CM, Grohmann C, Deiters A (2010) Small molecule modifiers of microRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma. J Am Chem Soc 132:7976–7981CrossRefGoogle Scholar
  121. 121.
    Deiters A (2010) Small molecule modifiers of the microRNA and RNA interference pathway. AAPS J 12:51–60CrossRefGoogle Scholar
  122. 122.
    Bose D, Jayaraj G, Suryawanshi H, Agarwala P, Pore SK, Banerjee R, Maiti S (2012) The tuberculosis drug streptomycin as a potential cancer therapeutic: inhibition of miR-21 function by directly targeting its precursor. Angew Chem Int Ed Engl 51:1019–1023CrossRefGoogle Scholar
  123. 123.
    Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139CrossRefGoogle Scholar
  124. 124.
    Pandey S, Agarwala P, Jayaraj GG, Gargallo R, Maiti S (2015) The RNA stem-loop to G-quadruplex equilibrium controls mature microRNA production inside the cell. Biochemistry 54:7067–7078CrossRefGoogle Scholar
  125. 125.
    Mirihana Arachchilage G, Dassanayake AC, Basu S (2015) A potassium ion-dependent RNA structural switch regulates human pre-miRNA 92b maturation. Chem Biol 22:262–272CrossRefGoogle Scholar
  126. 126.
    Stefanovic S, Bassell GJ, Mihailescu MR (2015) G quadruplex RNA structures in PSD-95 mRNA: potential regulators of miR-125a seed binding site accessibility. RNA 21:48–60CrossRefGoogle Scholar
  127. 127.
    Young LS, Rickinson AB (2004) Epstein-Barr virus: 40 years on. Nat Rev Cancer 4:757–768CrossRefGoogle Scholar
  128. 128.
    Kanda T, Kamiya M, Maruo S, Iwakiri D, Takada K (2007) Symmetrical localization of extrachromosomally replicating viral genomes on sister chromatids. J Cell Sci 120:1529–1539CrossRefGoogle Scholar
  129. 129.
    Yates JL, Warren N, Sugden B (1985) Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature 313:812–815CrossRefGoogle Scholar
  130. 130.
    Snudden DK, Hearing J, Smith PR, Grasser FA, Griffin BE (1994) EBNA-1, the major nuclear antigen of Epstein-Barr virus, resembles ‘RGG’ RNA binding proteins. EMBO J 13:4840–4847Google Scholar
  131. 131.
    Norseen J, Johnson FB, Lieberman PM (2009) Role for G-quadruplex RNA binding by Epstein-Barr virus nuclear antigen 1 in DNA replication and metaphase chromosome attachment. J Virol 83:10336–10346CrossRefGoogle Scholar
  132. 132.
    Wang SR, Zhang QY, Wang JQ, Ge XY, Song YY, Wang YF, Li XD, Fu BS, Xu GH, Shu B, Gong P, Zhang B, Tian T, Zhou X (2016) Chemical targeting of a G-quadruplex RNA in the Ebola Virus L gene. Cell Chem Biol 23:1113–1122CrossRefGoogle Scholar
  133. 133.
    Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J (2007) Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318:798–801CrossRefGoogle Scholar
  134. 134.
    Luke B, Lingner J (2009) TERRA: telomeric repeat-containing RNA. EMBO J 28:2503–2510CrossRefGoogle Scholar
  135. 135.
    Xu Y, Suzuki Y, Ito K, Komiyama M (2010) Telomeric repeat-containing RNA structure in living cells. Proc Natl Acad Sci U S A 107:14579–14584CrossRefGoogle Scholar
  136. 136.
    Lopez de Silanes I, Stagno d’Alcontres M, Blasco MA (2010) TERRA transcripts are bound by a complex array of RNA-binding proteins. Nat Commun 1:33Google Scholar
  137. 137.
    Booy EP, Meier M, Okun N, Novakowski SK, Xiong S, Stetefeld J, McKenna SA (2012) The RNA helicase RHAU (DHX36) unwinds a G4-quadruplex in human telomerase RNA and promotes the formation of the P1 helix template boundary. Nucleic Acids Res 40:4110–4124CrossRefGoogle Scholar
  138. 138.
    Bugaut A, Rodriguez R, Kumari S, Hsu ST, Balasubramanian S (2010) Small molecule-mediated inhibition of translation by targeting a native RNA G-quadruplex. Org Biomol Chem 8:2771–2776CrossRefGoogle Scholar
  139. 139.
    van Steensel B, Smogorzewska A, de Lange T (1998) TRF2 protects human telomeres from end-to-end fusions. Cell 92:401–413CrossRefGoogle Scholar
  140. 140.
    Bai Y, Lathia JD, Zhang P, Flavahan W, Rich JN, Mattson MP (2014) Molecular targeting of TRF2 suppresses the growth and tumorigenesis of glioblastoma stem cells. Glia 62:1687–1698CrossRefGoogle Scholar
  141. 141.
    Gomez D, Guedin A, Mergny JL, Salles B, Riou JF, Teulade-Fichou MP, Calsou P (2010) A G-quadruplex structure within the 5'-UTR of TRF2 mRNA represses translation in human cells. Nucleic Acids Res 38:7187–7198CrossRefGoogle Scholar
  142. 142.
    Biffi G, Tannahill D, Balasubramanian S (2012) An intramolecular G-quadruplex structure is required for binding of telomeric repeat-containing RNA to the telomeric protein TRF2. J Am Chem Soc 134:11974–11976CrossRefGoogle Scholar
  143. 143.
    Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2:a001008CrossRefGoogle Scholar
  144. 144.
    Courtois S, Verhaegh G, North S, Luciani MG, Lassus P, Hibner U, Oren M, Hainaut P (2002) DeltaN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53. Oncogene 21:6722–6728CrossRefGoogle Scholar
  145. 145.
    Bourdon JC, Fernandes K, Murray-Zmijewski F, Liu G, Diot A, Xirodimas DP, Saville MK, Lane DP (2005) p53 isoforms can regulate p53 transcriptional activity. Genes Dev 19:2122–2137CrossRefGoogle Scholar
  146. 146.
    Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8:275–283CrossRefGoogle Scholar
  147. 147.
    Pehar M, O’Riordan KJ, Burns-Cusato M, Andrzejewski ME, del Alcazar CG, Burger C, Scrable H, Puglielli L (2010) Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death. Aging Cell 9:174–190CrossRefGoogle Scholar
  148. 148.
    Gemignani F, Moreno V, Landi S, Moullan N, Chabrier A, Gutierrez-Enriquez S, Hall J, Guino E, Peinado MA, Capella G, Canzian F (2004) A TP53 polymorphism is associated with increased risk of colorectal cancer and with reduced levels of TP53 mRNA. Oncogene 23:1954–1956CrossRefGoogle Scholar
  149. 149.
    Quante T, Otto B, Brazdova M, Kejnovska I, Deppert W, Tolstonog GV (2012) Mutant p53 is a transcriptional co-factor that binds to G-rich regulatory regions of active genes and generates transcriptional plasticity. Cell Cycle 11:3290–3303CrossRefGoogle Scholar
  150. 150.
    Dias N, Stein CA (2002) Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides. Eur J Pharm Biopharm 54:263–269CrossRefGoogle Scholar
  151. 151.
    Kang MH, Reynolds CP (2009) Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15:1126–1132CrossRefGoogle Scholar
  152. 152.
    Sartorius UA, Krammer PH (2002) Upregulation of Bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines. Int J Cancer 97:584–592CrossRefGoogle Scholar
  153. 153.
    Dexheimer TS, Sun D, Hurley LH (2006) Deconvoluting the structural and drug-recognition complexity of the G-quadruplex-forming region upstream of the bcl-2 P1 promoter. J Am Chem Soc 128:5404–5415CrossRefGoogle Scholar
  154. 154.
    Rzuczek SG, Pilch DS, Liu A, Liu L, LaVoie EJ, Rice JE (2010) Macrocyclic pyridyl polyoxazoles: selective RNA and DNA G-quadruplex ligands as antitumor agents. J Med Chem 53:3632–3644CrossRefGoogle Scholar
  155. 155.
    Katsuda Y, Sato S, Asano L, Morimura Y, Furuta T, Sugiyama H, Hagihara M, Uesugi M (2016) A small molecule that represses translation of G-quadruplex-containing mRNA. J Am Chem Soc 138:9037–9040CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Satyaprakash Pandey
    • 1
  • Prachi Agarwala
    • 2
    • 3
  • Souvik Maiti
    • 2
    • 3
    • 4
    Email author
  1. 1.European Research Institute for the Biology of AgeingUniversity Medical Center Groningen (UMCG)GroningenThe Netherlands
  2. 2.Chemical and Systems Biology UnitCSIR-Institute of Genomics and Integrative BiologyNew DelhiIndia
  3. 3.Academy of Scientific and Innovative Research (AcSIR)New DelhiIndia
  4. 4.CSIR-National Chemical LaboratoryPuneIndia

Personalised recommendations