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DNA G-Quadruplexes and I-Motifs in Therapeutics and Diagnostics

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Chemical Biology of Nucleic Acids

Part of the book series: RNA Technologies ((RNATECHN))

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Abstract

G-quadruplex- and i-motif-based DNA oligomers are being investigated for their integration into therapeutic and diagnostic micro-assemblies. Examples include quadruplex-forming aptamers as potential anti-HIV agents, and serum-stable quadruplexes as carriers for delivering porphyrins into cancer cells for photodynamic therapy. The i-motifs from C-rich DNA find application in pH-triggered hydrogels that can carry agents like drugs, proteins, and polymers to their targets. The pH-dependent conformational dynamics of i-motifs also make them useful as biosensors for detecting pH changes in cellular microenvironments. Due to these and many other applications, and in an effort to present a compendia of recent uses of quadruplexes and i-motifs, this chapter will concern itself with formation of G-quadruplexes and i-motifs; their physical and chemical properties; the effects of molecular crowding and hydration on their structure and stability; and their application in therapeutics as drug targets, drug-delivery vehicles, and diagnostic tools.

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References

  • Arnott S, Chandrasekaran R, Marttila CM (1974) Structures for polyinosinic acid and polyguanylic acid. Biochem J 141:537–543

    PubMed Central  PubMed  CAS  Google Scholar 

  • Arola A, Vilar R (2008) Stabilisation of G-quadruplex DNA by small molecules. Curr Top Med Chem 8:1405–1415

    Article  PubMed  CAS  Google Scholar 

  • Balasubramanian S, Hurley LH, Neidle S (2011) Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? Nat Rev Drug Discov 10:261–275

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Bates PJ, Laber DA, Miller DM et al (2009) Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. Exp Mol Pathol 86:151–164

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Bejugam M, Sewitz S, Shirude PS et al (2007) Trisubstituted isoalloxazines as a new class of G-quadruplex binding ligands: small molecule regulation of c-kit oncogene expression. J Am Chem Soc 129:12926–12927

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Biffi G, Tannahill D, McCafferty J et al (2013) Quantitative visualization of DNA G-quadruplex structures in human cells. Nat Chem 5:182–186

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Blackburn EH (2000) Telomere states and cell fates. Nature 408:53–56

    Article  PubMed  CAS  Google Scholar 

  • Bock LC, Griffin LC, Latham JA et al (1992) Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature 355:564–566

    Article  PubMed  CAS  Google Scholar 

  • Brooks TA, Kendrick S, Hurley LH (2010) Making sense of G-quadruplex and i-motif functions in oncogene promoters. FEBS J 277:3459–3469

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Brown DM, Gray DM, Patrick MH et al (1985) Photochemical demonstration of stacked C · C base pairs in a novel DNA secondary structure. Biochemistry 24:1676–1683

    Article  PubMed  CAS  Google Scholar 

  • Burge S, Parkinson GN, Hazel P et al (2006) Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res 34:5402–5415

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Burger AM, Dai F, Schultes CM et al (2005) The G-quadruplex-interactive molecule BRACO-19 inhibits tumor growth, consistent with telomere targeting and interference with telomerase function. Cancer Res 65:1489–1496

    Article  PubMed  CAS  Google Scholar 

  • Campbell NH, Neidle S (2012) G-quadruplexes and metal ions. In: Sigel A, Sigel H, Sigel RK (eds) Interplay between metal ions and nucleic acids. Springer, Netherlands, pp 119–134

    Chapter  Google Scholar 

  • Chan SW, Blackburn EH (2002) New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin. Oncogene 21:553–563

    Article  PubMed  CAS  Google Scholar 

  • Chen JL, Sperry J, Ip NY et al (2011) Natural products targeting telomere maintenance. Med Chem Commun 2:229–245

    Article  CAS  Google Scholar 

  • Chen C, Li M, Xing Y et al (2012) Study of pH-induced folding and unfolding kinetics of the DNA i-motif by stopped-flow circular dichroism. Langmuir 28:17743–17748

    Article  PubMed  CAS  Google Scholar 

  • Chen C, Zhou L, Geng J et al (2013) Photosensitizer‐incorporated quadruplex DNA‐gated nanovechicles for light‐triggered. Targeted dual drug delivery to cancer cells. Small. doi:10.1002/smll.201201916:

    Google Scholar 

  • Cheng E, Xing Y, Chen P et al (2009) A pH‐triggered, fast‐responding DNA hydrogel. Angew Chem 121:7796–7799

    Article  Google Scholar 

  • Counter CM, Hahn WC, Wei W et al (1998) Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc Natl Acad Sci USA 95:14723–14728

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • De Lange T (1994) Activation of telomerase in a human tumor. Proc Natl Acad Sci USA 91:2882

    Article  PubMed Central  PubMed  Google Scholar 

  • Dhakal S, Cui Y, Koirala D et al (2013) Structural and mechanical properties of individual human telomeric G-quadruplexes in molecularly crowded solutions. Nucleic Acids Res 41:3915–3923

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Drygin D, Siddiqui-Jain A, O’Brien S et al (2009) Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. Cancer Res 69:7653–7661

    Article  PubMed  CAS  Google Scholar 

  • Düchler M (2012) G-quadruplexes: targets and tools in anticancer drug design. J Drug Target 20:389–400

    Article  PubMed  CAS  Google Scholar 

  • Gellert M, Lipsett MN, Davies DR (1962) Helix formation by guanylic acid. Proc Natl Acad Sci USA 48:2013–2018

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Gowan SM, Heald R, Stevens MF et al (2001) Potent inhibition of telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexes. Mol Pharmacol 60:981–988

    PubMed  CAS  Google Scholar 

  • Grütter MG, Priestle JP, Rahuel J et al (1990) Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition. EMBO J 9:2361–2365

    PubMed Central  PubMed  Google Scholar 

  • Guedin A, Gros J, Alberti P et al (2010) How long is too long? Effect of loop size on G-quadruplex stability. Nucleic Acids Res 38:7858–7868

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Guittat L, De Cian A, Rosu F et al (2005) Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro. Biochim Biophys Acta 1724:375–384

    Article  PubMed  CAS  Google Scholar 

  • Han H, Hurley LH (2000) G-quadruplex DNA: a potential target for anti-cancer drug design. Trends Pharmacol Sci 21:136–141

    Article  PubMed  CAS  Google Scholar 

  • Han H, Hurley LH, Salazar M (1999) A DNA polymerase stop assay for G-quadruplex-interactive compounds. Nucleic Acids Res 27:537–542

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621

    Article  PubMed  CAS  Google Scholar 

  • Hazel P, Huppert J, Balasubramanian S et al (2004) Loop-length-dependent folding of G-quadruplexes. J Am Chem Soc 126:16405–16415

    Article  PubMed  CAS  Google Scholar 

  • Hu K, Huang Y, Zhao S et al (2012) Ultrasensitive detection of potassium ions based on target induced DNA conformational switch enhanced fluorescence polarization. Analyst 137:2770–2773

    Article  PubMed  CAS  Google Scholar 

  • Huang C, Chang H (2008) Aptamer-based fluorescence sensor for rapid detection of potassium ions in urine. Chem Commun 12:1461–1463

    Article  CAS  Google Scholar 

  • Hud NV, Smith FW, Anet FA et al (1996) The selectivity for K versus Na in DNA quadruplexes is dominated by relative free energies of hydration: a thermodynamic analysis by 1H NMR. Biochemistry 35:15383–15390

    Article  PubMed  CAS  Google Scholar 

  • Hurley LH, Wheelhouse RT, Sun D et al (2000) G-quadruplexes as targets for drug design. Pharmacol Ther 85:141–158

    Article  PubMed  CAS  Google Scholar 

  • Kan Z, Yao Y, Wang P et al (2006) Molecular crowding induces telomere G‐quadruplex formation under salt‐deficient conditions and enhances its competition with duplex formation. Angew Chem Int Ed 45:1629–1632

    Article  CAS  Google Scholar 

  • Keum J, Bermudez H (2012) DNA-based delivery vehicles: pH-controlled disassembly and cargo release. Chem Commun 48:12118–12120

    Article  CAS  Google Scholar 

  • Kim NW, Piatyszek MA, Prowse KR et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015

    Article  PubMed  CAS  Google Scholar 

  • Kim M, Gleason-Guzman M, Izbicka E et al (2003) The different biological effects of telomestatin and TMPyP4 can be attributed to their selectivity for interaction with intramolecular or intermolecular G-quadruplex structures. Cancer Res 63:3247–3256

    PubMed  CAS  Google Scholar 

  • Kypr J, Kejnovská I, Renčiuk D et al (2009) Circular dichroism and conformational polymorphism of DNA. Nucleic Acids Res 37:1713–1725

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Lane AN, Chaires JB, Gray RD et al (2008) Stability and kinetics of G-quadruplex structures. Nucleic Acids Res 36:5482–5515

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Langridge R, Rich A (1963) Molecular structure of helical polycytidylic acid. Nature 198:725–728

    Article  PubMed  CAS  Google Scholar 

  • Li W, Feng L, Ren J et al (2012a) Visual detection of glucose using conformational switch of i‐motif DNA and non‐crosslinking gold nanoparticles. Chem Eur J 18:12637–12642

    Article  PubMed  CAS  Google Scholar 

  • Li C, Zhu L, Zhu Z et al (2012b) Backbone modification promotes peroxidase activity of G-quadruplex-based DNAzyme. Chem Commun 48:8347–8349

    Article  CAS  Google Scholar 

  • Liu D, Bruckbauer A, Abell C et al (2006) A reversible pH-driven DNA nanoswitch array. J Am Chem Soc 128:2067–2071

    Article  PubMed  CAS  Google Scholar 

  • Liu C, Huang C, Chang H (2009) Highly selective DNA-based sensor for lead (II) and mercury (II) ions. Anal Chem 81:2383–2387

    Article  PubMed  CAS  Google Scholar 

  • Longhese MP (2008) DNA damage response at functional and dysfunctional telomeres. Genes Dev 22:125–140

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Magbanua E, Zivkovic T, Hansen B et al (2013) d (GGGT) 4 and r (GGGU) 4 are both HIV-1 inhibitors and interleukin-6 receptor aptamers. RNA Biol 10:216–227

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Mergny J, Lacroix L (1998) Kinetics and thermodynamics of i-DNA formation: phosphodiester versus modified oligodeoxynucleotides. Nucleic Acids Res 26:4797–4803

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Miyoshi D, Sugimoto N (2008) Molecular crowding effects on structure and stability of DNA. Biochimie 90:1040–1051

    Article  PubMed  CAS  Google Scholar 

  • Miyoshi D, Nakao A, Sugimoto N (2002) Molecular crowding regulates the structural switch of the DNA G-quadruplex. Biochemistry 41:15017–15024

    Article  PubMed  CAS  Google Scholar 

  • Miyoshi D, Inoue M, Sugimoto N (2006) DNA logic gates based on structural polymorphism of telomere DNA molecules responding to chemical input signals. Angew Chem Int Ed 45:7716–7719

    Article  CAS  Google Scholar 

  • Modi S, Wani AH, Krishnan Y (2006) The PNA–DNA hybrid I-motif: implications for sugar–sugar contacts in i-motif tetramerization. Nucleic Acids Res 34:4354–4363

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Modi S, Swetha M, Goswami D et al (2009) A DNA nanomachine that maps spatial and temporal pH changes inside living cells. Nat Nanotechnol 4:325–330

    Article  PubMed  CAS  Google Scholar 

  • Moorhouse AD, Santos AM, Gunaratnam M et al (2006) Stabilization of G-quadruplex DNA by highly selective ligands via click chemistry. J Am Chem Soc 128:15972–15973

    Article  PubMed  CAS  Google Scholar 

  • Moyzis RK, Buckingham JM, Cram LS et al (1988) A highly conserved repetitive DNA sequence, (TTAGGG) n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA 85:6622–6626

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Neidle S, Balasubramanian S (2006) Quadruplex nucleic acids. RSC Publishing, London

    Book  Google Scholar 

  • Neidle S, Parkinson G (2002) Telomere maintenance as a target for anticancer drug discovery. Nat Rev Drug Discov 1:383–393

    Article  PubMed  CAS  Google Scholar 

  • Neidle S, Read MA (2000) G‐quadruplexes as therapeutic targets. Biopolymers 56:195–208

    Article  PubMed  CAS  Google Scholar 

  • Rachwal PA, Findlow IS, Werner JM et al (2007) Intramolecular DNA quadruplexes with different arrangements of short and long loops. Nucleic Acids Res 35:4214–4222

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Rajendran A, Nakano S, Sugimoto N (2010) Molecular crowding of the cosolutes induces an intramolecular i-motif structure of triplet repeat DNA oligomers at neutral pH. Chem Commun 46:1299–1301

    Article  CAS  Google Scholar 

  • Randazzo A, Esposito V, Ohlenschläger O et al (2004) NMR solution structure of a parallel LNA quadruplex. Nucleic Acids Res 32:3083–3092

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Raymond E, Sun D, Chen S et al (1996) Agents that target telomerase and telomeres. Curr Opin Biotechnol 7:583

    Article  PubMed  CAS  Google Scholar 

  • Read M, Harrison RJ, Romagnoli B et al (2001) Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors. Proc Natl Acad Sci USA 98:4844–4849

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Risitano A, Fox KR (2004) Influence of loop size on the stability of intramolecular DNA quadruplexes. Nucleic Acids Res 32:2598–2606

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Sacks DB (2011) A1C versus glucose testing: a comparison. Diabetes Care 34:518–523

    Article  PubMed Central  PubMed  Google Scholar 

  • Saretzki G (2003) Telomerase inhibition as cancer therapy. Cancer Lett 194:209–219

    Article  PubMed  CAS  Google Scholar 

  • Seenisamy J, Bashyam S, Gokhale V et al (2005) Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure. J Am Chem Soc 127:2944–2959

    Article  PubMed  CAS  Google Scholar 

  • Sharma NK, Ganesh KN (2005) PNA C–C i-motif: superior stability of PNA TC8 tetraplexes compared to DNA TC8 tetraplexes at low pH. Chem Commun 34:4330–4332

    Article  CAS  Google Scholar 

  • Shieh Y, Yang S, Wei M et al (2010) Aptamer-based tumor-targeted drug delivery for photodynamic therapy. ACS Nano 4:1433–1442

    Article  PubMed  CAS  Google Scholar 

  • Shum K, Zhou J, Rossi JJ (2013) Nucleic acid aptamers as potential therapeutic and diagnostic agents for lymphoma. J Cancer Ther 4:872–890

    Article  Google Scholar 

  • Siddiqui-Jain A, Grand CL, Bearss DJ et al (2002) Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc Natl Acad Sci USA 99:11593–11598

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Smirnov I, Shafer RH (2000) Effect of loop sequence and size on DNA aptamer stability. Biochemistry 39:1462–1468

    Article  PubMed  CAS  Google Scholar 

  • Smirnov IV, Shafer RH (2007) Electrostatics dominate quadruplex stability. Biopolymers 85:91–101

    Article  PubMed  CAS  Google Scholar 

  • Steinert S, Shay JW, Wright WE (2004) Modification of subtelomeric DNA. Mol Cell Biol 24:4571–4580

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Sun D, Hurley LH (2009) The importance of negative superhelicity in inducing the formation of G-quadruplex and i-motif structures in the c-Myc promoter: implications for drug targeting and control of gene expression. J Med Chem 52:2863–2874

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Sun C, Wang X, Yang X et al (2013) A label-free electrochemical aptasensor for sensitive thrombin detection in whole blood. Electrochim Acta 106:327–332

    Article  CAS  Google Scholar 

  • Teng Y, Girvan AC, Casson LK et al (2007) AS1411 alters the localization of a complex containing protein arginine methyltransferase 5 and nucleolin. Cancer Res 67:10491–10500

    Article  PubMed  CAS  Google Scholar 

  • Zhang AYQ, Bugaut A, Balasubramanian S (2011) A Sequence-Independent analysis of the loop length dependence of intramolecular RNA G-quadruplex stability and topology. Biochemistry 50:7251–7258

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Zhao Y, Du Z, Li N (2007) Extensive selection for the enrichment of G4 DNA motifs in transcriptional regulatory regions of warm blooded animals. FEBS Lett 581:1951–1956

    Article  PubMed  CAS  Google Scholar 

  • Zhou J, Zhu X, Lu Y et al (2005) Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines. Oncogene 25:503–511

    Google Scholar 

  • Zhou J, Wei C, Jia G et al (2010) Formation of i-motif structure at neutral and slightly alkaline pH. Mol Biosyst 6:580–586

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Randy M. Wadkins .

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Bhavsar-Jog, Y.P., Reilly, S.M., Wadkins, R.M. (2014). DNA G-Quadruplexes and I-Motifs in Therapeutics and Diagnostics. In: Erdmann, V., Markiewicz, W., Barciszewski, J. (eds) Chemical Biology of Nucleic Acids. RNA Technologies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54452-1_24

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