G-quadruplex formation of oligonucleotides containing ALS and FTD related GGGGCC repeat

Abstract

A largely increased number of GGGGCC repeats located in the non-coding region of C9orf72 gene have been identified as the leading cause of two related neurological disorders, familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We examined G-quadruplex forming ability of GGGGCC-repeat containing oligonucleotides with four guanine tracts chosen as the smallest possible model to form a unimolecular G-quadruplex. These oligonucleotides are readily to folded into G-quadruplexes in the presence of K⁺ ions. However, the formation of multiple structures makes structural analysis challenging and time consuming. We observed that flanking sequences on 5'- and 3'-ends as well as mutations of loop residues have a profound effect on folding. Sequence d[(G₄C₂)₃G₄] was chosen for further scrutiny and optimization of nuclear magnetic resonance (NMR) spectroscopic properties with dG to 8Br-dG substitutions at specific positions in the sequence under different folding conditions. Expectedly, folding into desired predominant topology is facilitated when substituted residue adopted a syn conformation in the naturally-occurring structure. Single dG to 8Br-dG substitution at position 21 and fine tuning of folding conditions facilitate folding of d[(G₄C₂)₃GG^BrGG] into (mostly) a single G-quadruplex, and thus enable determination of its high-resolution structure by high-field NMR.

Graphical abstract

Keywords

G-quadruplex / GGGGCC / NMR / ALS/FTD / polymorphism

References

[1] Wu Y, Brosh R M Jr. G-quadruplex nucleic acids and human disease. FEBS Journal, 2010, 277(17): 3470–3488

[2] Murat P, Balasubramanian S. Existence and consequences of G-quadruplex structures in DNA. Current Opinion in Genetics & Development, 2014, 25: 22–29

[3] Tarsounas M, Tijsterman M. Genomes and G-quadruplexes: For better or for worse. Journal of Molecular Biology, 2013, 425(23): 4782–4789

[4] Huppert J L, Balasubramanian S. G-quadruplexes in promoters throughout the human genome. Nucleic Acids Research, 2006, 35(2): 406–413

[5] Verma A, Yadav V K, Basundra R, Kumar A, Chowdhury S. Evidence of genome-wide G4 DNA-mediated gene expression in human cancer cells. Nucleic Acids Research, 2009, 37(13): 4194–4204

[6] Bugaut A, Balasubramanian S. 5'-UTR RNA G-quadruplexes: Translation regulation and targeting. Nucleic Acids Research, 2012, 40(11): 4727–4741

[7] Yuan L, Tian T, Chen Y, Yan S, Xing X, Zhang Z, Zhai Q, Xu L, Wang S, Weng X, Yuan B, Feng Y, Zhou X. Existence of G-quadruplex structures in promoter region of oncogenes confirmed by G-quadruplex DNA cross-linking strategy. Scientific Reports, 2013, 3: 1811

[8] Phan A T, Modi Y S, Patel D J. Propeller-type parallel-stranded G-quadruplexes in the human c-myc promoter. Journal of the American Chemical Society, 2004, 126(28): 8710–8716

[9] Ambrus A, Chen D, Dai J, Jones R A, Yang D. Solution structure of the biologically relevant G-quadruplex element in the human c-MYC promoter. Implications for G-quadruplex stabilization. Biochemistry, 2005, 44(6): 2048–2058

[10] Schwab M. MYCN in neuronal tumours. Cancer Letters, 2004, 204(2): 179–187

[11] Brooks T A, Hurley L H. The role of supercoiling in transcriptional control of MYC and its importance in molecular therapeutics. Nature Reviews. Cancer, 2009, 9(12): 849–861

[12] Trajkovski M, da Silva M W, Plavec J. Unique structural features of interconverting monomeric and dimeric G-quadruplexes adopted by a sequence from the intron of the N-myc gene. Journal of the American Chemical Society, 2012, 134(9): 4132–4141

[13] Rankin S, Reszka A P, Huppert J, Zloh M, Parkinson G N, Todd A K, Ladame S, Balasubramanian S, Neidle S. Putative DNA quadruplex formation within the human c-kit oncogene. Journal of the American Chemical Society, 2005, 127(30): 10584–10589

[14] Cogoi S, Xodo L E. G-quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription. Nucleic Acids Research, 2006, 34(9): 2536–2549

[15] Sun D, Guo K, Rusche J J, Hurley L H. Facilitation of a structural transition in the polypurine/polypyrimidine tract within the proximal promoter region of the human VEGF gene by the presence of potassium and G-quadruplex-interactive agents. Nucleic Acids Research, 2005, 33(18): 6070–6080

[16] Dai J, Dexheimer T S, Chen D, Carver M, Ambrus A, Jones R A, Yang D. An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution. Journal of the American Chemical Society, 2006, 128(4): 1096–1098

[17] Tong X, Lan W, Zhang X, Wu H, Liu M, Cao C. Solution structure of all parallel G-quadruplex formed by the oncogene RET promoter sequence. Nucleic Acids Research, 2011, 39(15): 6753–6763

[18] Fry M, Loeb L A. The fragile X syndrome d(CGG)n nucleotide repeats form a stable tetrahelical structure. Proceedings of the National Academy of Sciences of the United States of America, 1994, 91(11): 4950–4954

[19] Li J L, Harrison R J, Reszka A P, Brosh R M Jr, Bohr V A, Neidle S, Hickson I D. Inhibition of the Bloom′s and Werner′s syndrome helicases by G-quadruplex interacting ligands. Biochemistry, 2001, 40(50): 15194–15202

[20] Lillo P, Hodges J R. Frontotemporal dementia and motor neurone disease: Overlapping clinic-pathological disorders. Journal of Clinical Neuroscience, 2009, 16(9): 1131–1135

[21] Rutherford N J, Heckman M G, Dejesus-Hernandez M, Baker M C, Ortolaza-Soto A I, Rayaprolu S. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype. Neurobiol Aging, 2012, 332950

[22] DeJesus-Hernandez M, Mackenzie I R, Boeve B F, Boxer A L, Baker M, Rutherford N J, Nicholson A M, Finch N C A, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung G Y R, Karydas A, Seeley W W, Josephs K A, Coppola G, Geschwind D H, Wszolek Z K, Feldman H, Knopman D S, Petersen R C, Miller B L, Dickson D W, Boylan K B, Graff-Radford N R, Rademakers R. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron, 2011, 72(2): 245–256

[23] Renton A E, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs J R, Schymick J C, Laaksovirta H, van Swieten J C, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes A M, Kaganovich A, Scholz S W, Duckworth J, Ding J, Harmer D W, Hernandez D G, Johnson J O, Mok K, Ryten M, Trabzuni D, Guerreiro R J, Orrell R W, Neal J, Murray A, Pearson J, Jansen I E, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister J B, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls M A, Peuralinna T, Jansson L, Isoviita V M, Kaivorinne A L, Hölttä-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chiò A, Restagno G, Borghero G, Sabatelli M, Heckerman D, Rogaeva E, Zinman L, Rothstein J D, Sendtner M, Drepper C, Eichler E E, Alkan C, Abdullaev Z, Pack S D, Dutra A, Pak E, Hardy J, Singleton A, Williams N M, Heutink P, Pickering-Brown S, Morris H R, Tienari P J, Traynor B J. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron, 2011, 72(2): 257–268

[24] Haeusler A R, Donnelly C J, Periz G, Simko E A J, Shaw P G, Kim M S, Maragakis N J, Troncoso J C, Pandey A, Sattler R, Rothstein J D, Wang J. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature, 2014, 507(7491): 195–200

[25] Šket P, Pohleven J, Kovanda A, Stalekar M, Zupunski V , Zalar M,Plavec J, Rogelj B. Characterization of DNA G-quadruplex species forming from C9ORF72 G4C2-expanded repeats associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Neurobiology of Aging, 2015, 36(2): 1091–1096

[26] Fratta P, Mizielinska S, Nicoll A, Zloh M, Fisher E M C, Parkinson G N, Isaacs A M. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Scientific Reports, 2012, 2: 1016

[27] Reddy K, Zamiri B, Stanley S Y, Macgregor R B Jr, Pearson C E. The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures. Journal of Biological Chemistry, 2013, 288(14): 9860–9866

[28] Lee Y B, Chen H J, Peres J N, Gomez-Deza J, Attig J, Stalekar M, Troakes C, Nishimura A L, Scotter E L, Vance C, Adachi Y, Sardone V, Miller J W, Smith B N, Gallo J M, Ule J, Hirth F, Rogelj B, Houart C, Shaw C E. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Reports, 2013, 5(5): 1178–1186

[29] Renoux A J, Todd P K. Neurodegeneration the RNA way. Progress in Neurobiology, 2012, 97(2): 173–189

[30] Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson D L, Li H, Hales C M, Gearing M, Wingo T S, Jin P. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(19): 7778–7783

[31] Donnelly C J, Zhang P W, Pham J T, Haeusler A R, Mistry N A, Vidensky S, Daley E L, Poth E M, Hoover B, Fines D M, Maragakis N, Tienari P J, Petrucelli L, Traynor B J, Wang J, Rigo F, Bennett C F, Blackshaw S, Sattler R, Rothstein J D. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron, 2013, 80(2): 415–428

[32] Gendron T F, Cosio D M, Petrucelli L. c9RAN translation: A potential therapeutic target for the treatment of amyotrophic lateral sclerosis and frontotemporal dementia. Expert Opinion on Therapeutic Targets, 2013, 17(9): 991–995

[33] Jovicic A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada S B, Paul J W, Sun S, Herdy J R, Bieri G, Kramer N J, Gage F H, Van Den Bosch L, Robberecht W, Gitler A D. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nature Neuroscience, 2015, 18(9): 1226–1229

[34] Mizielinska S, Gronke S, Niccoli T, Ridler C E, Clayton E L, Devoy A, Moens T, Norona F E, Woollacott I O C, Pietrzyk J, Cleverley K, Nicoll A J, Pickering-Brown S, Dols J, Cabecinha M, Hendrich O, Fratta P, Fisher E M C, Partridge L, Isaacs A M. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science, 2014, 345(6201): 1192–1194

[35] Mori K, Weng S M, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar H A, Cruts M, Van Broeckhoven C, Haass C, Edbauer D. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science, 2013, 339(6125): 1335–1338

[36] Marusic M, Veedu R N, Wengel J, Plavec J. G-rich VEGF aptamer with locked and unlocked nucleic acid modifications exhibits a unique G-quadruplex fold. Nucleic Acids Research, 2013, 41(20): 9524–9536

[37] Mukundan V T, Phan A T. Bulges in G-quadruplexes: Broadening the definition of G-quadruplex-forming sequences. Journal of the American Chemical Society, 2013, 135(13): 5017–5028

[38] Nielsen J T, Arar K, Petersen M. Solution structure of a locked nucleic acid modified quadruplex: Introducing the V4 folding topology. Angewandte Chemie International Edition, 2009, 48(17): 3099–3103

[39] Wei D, Todd A K, Zloh M, Gunaratnam M, Parkinson G N, Neidle S. Crystal structure of a promoter sequence in the B-raf gene reveals an intertwined dimer quadruplex. Journal of the American Chemical Society, 2013, 135(51): 19319–19329

[40] Kocman V, Plavec J. A tetrahelical DNA fold adopted by tandem repeats of alternating GGG and GCG tracts. Nature Communications, 2014, 5: 5831

[41] Marusic M, Sket P, Bauer L, Viglasky V, Plavec J. Solution-state structure of an intramolecular G-quadruplex with propeller, diagonal and edgewise loops. Nucleic Acids Research, 2012, 40(14): 6946–6956

[42] Phan A T, Kuryavyi V, Ma J B, Faure A, Andreola M L, Patel D J. An interlocked dimeric parallel-stranded DNA quadruplex: A potent inhibitor of HIV-1 integrase. Proceedings of the National Academy of Sciences of the United States of America, 2005, 102(3): 634–639

[43] Trajkovski M, Morel E, Hamon F, Bombard S, Teulade-Fichou M P, Plavec J. Interactions of Pt-ttpy with G-quadruplexes originating from promoter region of the c-myc gene deciphered by NMR and gel electrophoresis analysis. Chemistry (Weinheim an der Bergstrasse, Germany), 2015, 21(21): 7798–7807

[44] Šket P, Korbar T, Plavec J. Influence of 3'-3' inversion of polarity site within d (TGGGGT) on inter quartet cation binding. Journal of Molecular Structure, 2014, 1075: 49–52

[45] Čeru S, Sket P, Prislan I, Lah J, Plavec J. A new pathway of DNA G-Quadruplex formation. Angewandte Chemie International Edition, 2014, 53(19): 4881–4884

[46] Tlučková K, Marusic M, Tothova P, Bauer L, Sket P, Plavec J, Viglasky V. Human papillomavirus G-quadruplexes. Biochemistry, 2013, 52(41): 7207–7216

[47] Trajkovski M, Plavec J. Assessing roles of cations in G-quadruplex-based nanowires by NMR. Journal of Physical Chemistry C, 2012, 116(44): 23821–23825

[48] Sket P, Virgilio A, Esposito V, Galeone A, Plavec J. Strand directionality affects cation binding and movement within tetramolecular G-quadruplexes. Nucleic Acids Research, 2012, 40(21): 11047–11057

[49] Wang Y, Patel D J. Guanine residues in d(T2AG3) and d(T2G4) form parallel-stranded potassium cation stabilized G-quadruplexes with anti glycosidic torsion angles in solution. Biochemistry, 1992, 31(35): 8112–8119

[50] Uddin M K, Kato Y, Takagi Y, Mikuma T, Taira K. Phosphorylation at 5' end of guanosine stretches inhibits dimerization of G-quadruplexes and formation of a G-quadruplex interferes with the enzymatic activities of DNA enzymes. Nucleic Acids Research, 2004, 32(15): 4618–4629

[51] Mukundan V T, Do N Q, Phan A T. HIV-1 integrase inhibitor T30177 forms a stacked dimeric G-quadruplex structure containing bulges. Nucleic Acids Research, 2011, 39(20): 8984–8991

[52] Zhang Z, Dai J, Veliath E, Jones R A, Yang D. Structure of a two-G-tetrad intramolecular G-quadruplex formed by a variant human telomeric sequence in K⁺ solution: Insights into the interconversion of human telomeric G-quadruplex structures. Nucleic Acids Research, 2010, 38(3): 1009–1021

[53] Črnugelj M, Sket P, Plavec J. Small change in a G-rich sequence, a dramatic change in topology: New dimeric G-quadruplex folding motif with unique loop orientations. Journal of the American Chemical Society, 2003, 125(26): 7866–7871

[54] Lu M, Guo Q, Kallenbach N R. Structure and stability of sodium and potassium complexes of dT4G4 and dT4G4T. Biochemistry, 1992, 31(9): 2455–2459

[55] Dai J X, Carver M, Punchihewa C, Jones R A, Yang D Z. Structure of the Hybrid-2 type intramolecular human telomeric G-quadruplex in K⁺ solution: Insights into structure polymorphism of the human telomeric sequence. Nucleic Acids Research, 2007, 35(15): 4927–4940

[56] Dai J X, Punchihewa C, Ambrus A, Chen D, Jones R A, Yang D Z. Structure of the intramolecular human telomeric G-quadruplex in potassium solution: A novel adenine triple formation. Nucleic Acids Research, 2007, 35(7): 2440–2450

[57] Sattin G, Artese A, Nadai M, Costa G, Parrotta L, Alcaro S, Palumbo M, Richter S N. Conformation and stability of intramolecular telomeric G-quadruplexes: Sequence effects in the loops. PLoS One, 2013, 8(12): e84113

[58] Phan A T, Patel D J. Two-repeat human telomeric d(TAGGGTTAGGGT) sequence forms interconverting parallel and antiparallel G-quadruplexes in solution: Distinct topologies, thermodynamic properties, and folding/unfolding kinetics. Journal of the American Chemical Society, 2003, 125(49): 15021–15027

[59] Zaitseva M, Kaluzhny D, Shchyolkina A, Borisova O, Smirnov I, Pozmogova G. Conformation and thermostability of oligonucleotide d(GGTTGGTGTGGTTGG) containing thiophosphoryl internucleotide bonds at different positions. Biophysical Chemistry, 2010, 146(1): 1–6

[60] Bonifacio L, Church F C, Jarstfer M B. Effect of locked-nucleic acid on a biologically active G-quadruplex. A structure-activity relationship of the thrombin aptamer. International Journal of Molecular Sciences, 2008, 9(3): 422–433

[61] Pasternak A, Hernandez F J, Rasmussen L M, Vester B, Wengel J. Improved thrombin binding aptamer by incorporation of a single unlocked nucleic acid monomer. Nucleic Acids Research, 2011, 39(3): 1155–1164

[62] Aviñó A, Mazzini S, Ferreira R, Gargallo R, Marquez V E, Eritja R. The effect on quadruplex stability of North-nucleoside derivatives in the loops of the thrombin-binding aptamer. Bioorganic & Medicinal Chemistry, 2012, 20(14): 4186–4193

[63] Pedersen E B, Nielsen J T, Nielsen C, Filichev V V. Enhanced anti-HIV-1 activity of G-quadruplexes comprising locked nucleic acids and intercalating nucleic acids. Nucleic Acids Research, 2011, 39(6): 2470–2481

[64] Luu K N, Phan A T, Kuryavyi V, Lacroix L, Patel D J. Structure of the human telomere in K⁺ solution: An intramolecular (3+1) G-quadruplex scaffold. Journal of the American Chemical Society, 2006, 128(30): 9963–9970

[65] Dai J, Carver M, Punchihewa C, Jones R A, Yang D. Structure of the Hybrid-2 type intramolecular human telomeric G-quadruplex in K⁺ solution: Insights into structure polymorphism of the human telomeric sequence. Nucleic Acids Research, 2007, 35(15): 4927–4940

[66] Lim K W, Amrane S, Bouaziz S, Xu W, Mu Y, Patel D J, Luu K N, Phan A T. Structure of the human telomere in K⁺ solution: A stable basket-type G-quadruplex with only two G-tetrad layers. Journal of the American Chemical Society, 2009, 131(12): 4301–4309

[67] Sagi J. G-quadruplexes incorporating modified constituents: A review. Journal of Biomolecular Structure & Dynamics, 2014, 32(3): 477–511

[68] Pradhan D, Hansen L H, Vester B, Petersen M. Selection of G-quadruplex folding topology with LNA-modified human telomeric sequences in K⁺ solution. Chemistry (Weinheim an der Bergstrasse, Germany), 2011, 17(8): 2405–2413

[69] Martín-Pintado N, Yahyaee-Anzahaee M, Deleavey G F, Portella G, Orozco M, Damha M J, González C. Dramatic effect of furanose C2' substitution on structure and stability: Directing the folding of the human telomeric quadruplex with a single fluorine atom. Journal of the American Chemical Society, 2013,135(14): 5344–5347

[70] Lech C J, Li Z, Heddi B, Phan A T. 2'-F-ANA-guanosine and 2'-F-guanosine as powerful tools for structural manipulation of G-quadruplexes. Chemical Communications (Cambridge), 2012, 48(93): 11425–11427

[71] Randazzo A, Esposito V, Ohlenschlager O, Ramachandran R, Mayola L. NMR solution structure of a parallel LNA quadruplex. Nucleic Acids Research, 2004, 32(10): 3083–3092

[72] Nielsen J T, Arar K, Petersen M. NMR solution structures of LNA (locked nucleic acid) modified quadruplexes. Nucleic Acids Research, 2006, 34(7): 2006–2014

[73] Randazzo A, Esposito V, Ohlenschlager O, Ramachandran R, Virgilio A, Mayol L. Structural studies on LNA quadruplexes. Nucleosides, Nucleotides & Nucleic Acids, 2005, 24(5-7): 795–800

[74] Dominick P K, Jarstfer M B. A conformationally constrained nucleotide analogue controls the folding topology of a DNA g-quadruplex. Journal of the American Chemical Society, 2004, 126(16): 5050–5051

[75] Sarma R H, Lee C H, Evans F E, Yathindra N, Sundaralingam M. Probing the interrelation between the glycosyl torsion, sugar pucker, and the backbone conformation in C(8) substituted adenine nucleotides by 1H and 1H-(31P) fast Fourier transform nuclear magnetic resonance methods and conformational energy calculations. Journal of the American Chemical Society, 1974, 96: 7337–7348

[76] Matsugami A, Xu Y, Noguchi Y, Sugiyama H, Katahira M. Structure of a human telomeric DNA sequence stabilized by 8-bromoguanosine substitutions, as determined by NMR in a K⁺ solution. FEBS Journal, 2007, 274(14): 3545–3556

[77] Lim K W, Ng V C, Martin-Pintado N, Heddi B, Phan A T. Structure of the human telomere in Na⁺ solution: An antiparallel (2+2) G-quadruplex scaffold reveals additional diversity. Nucleic Acids Research, 2013, 41(22): 10556–10562

[78] Brčić J, Plavec J. Solution structure of a DNA quadruplex containing ALS and FTD related GGGGCC repeat stabilized by 8-bromodeoxyguanosine substitution. Nucleic Acids Research, 2015, 43(17), 8590‒8600

[79] Wang Y, Patel D J. Solution structure of the human telomeric repeat d[AG3(T2AG3)3] G-tetraplex. Structure (London, England), 1993, 1(4): 263–282

[80] Parkinson G N, Lee M P, Neidle S. Crystal structure of parallel quadruplexes from human telomeric DNA. Nature, 2002, 417(6891): 876–880

[81] Lannan F M, Mamajanov I, Hud N V. Human telomere sequence DNA in water-free and high-viscosity solvents: G-Quadruplex folding governed by Kramers rate theory. Journal of the American Chemical Society, 2012, 134(37): 15324–15330

[82] Yan Y Y, Tan J H, Lu Y J, Yan S C, Wong K Y, Li D, Gu L Q, Huang Z S. G-Quadruplex conformational change driven by pH variation with potential application as a nanoswitch. Biochimica et Biophysica Acta, 2013, 1830: 4935–4942

[83] Xue Y, Kan Z Y, Wang Q, Yao Y, Liu J, Hao Y H, Tan Z. Human telomeric DNA forms parallel-stranded intramolecular G-quadruplex in K⁺ solution under molecular crowding condition. Journal of the American Chemical Society, 2007, 129(36): 11185–11191

[84] Yu H, Zhao C, Chen Y, Fu M, Ren J, Qu X. DNA loop sequence as the determinant for chiral supramolecular compound G-quadruplex selectivity. Journal of Medicinal Chemistry, 2010, 53(1): 492–498

[85] Webba da Silva M. Geometric formalism for DNA quadruplex folding. Chemistry (Weinheim an der Bergstrasse, Germany), 2007, 13(35): 9738–9745

[86] Karsisiotis A I, O′Kane C, Webba da Silva M. DNA quadruplex folding formalism—a tutorial on quadruplex topologies. Methods (San Diego, Calif.), 2013, 64(1): 28–35

[87] Yang D, Okamoto K. Structural insights into G-quadruplexes: towards new anticancer drugs. Future Medicinal Chemistry, 2010, 2(4): 619–646

[88] Dai J, Punchihewa C, Ambrus A, Chen D, Jones R A, Yang D. Structure of the intramolecular human telomeric G-quadruplex in potassium solution: A novel adenine triple formation. Nucleic Acids Research, 2007, 35(7): 2440–2450

Electronic Supplementary Material

Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s11705-016-1556-4 and is accessible for authorized users.

Acknowledgements

This work was supported by the Slovenian Research Agency (ARRS, Grant Nos. P1-0242 and J1-6733).

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