G-quadruplexes are noncanonical nucleic acid structures formed from stacked guanine tetrads. They are frequently used as building blocks and functional elements in fields such as synthetic biology and also thought to play widespread biological roles. G-quadruplexes are often studied as monomers, but can also form a variety of higher-order structures. This increases the structural and functional diversity of G-quadruplexes, and recent evidence suggests that it could also be biologically important. In this review, we describe the types of multimeric topologies adopted by G-quadruplexes and highlight what is known about their sequence requirements. We also summarize the limited information available about potential biological roles of multimeric G-quadruplexes and suggest new approaches that could facilitate future studies of these structures.

Department of Biochemistry and Microbiology University of Chemistry and Technology 166 28 Prague Czech Republic

The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences 166 10 Prague Czech Republic

Zobrazit více v PubMed

Rich A. DNA comes in many forms. Gene. 1993;135:99–109. doi: 10.1016/0378-1119(93)90054-7. PubMed DOI

Hu Y., Cecconello A., Idili A., Ricci F., Willner I. Triplex DNA nanostructures: From basic properties to applications. Angew. Chem. Int. Ed. Engl. 2017;56:15210–15233. doi: 10.1002/anie.201701868. PubMed DOI

Davis J.T. G-quartets 40 years later: From 5′-GMP to molecular biology and supramolecular chemistry. Angew. Chem. Int. Ed. Engl. 2004;43:668–698. doi: 10.1002/anie.200300589. PubMed DOI

Day H.A., Pavlou P., Waller Z.A. I-Motif DNA: Structure, stability and targeting with ligands. Bioorg. Med. Chem. 2014;22:4407–4418. doi: 10.1016/j.bmc.2014.05.047. PubMed DOI

Burge S., Parkinson G.N., Hazel P., Todd A.K., Neidle S. Quadruplex DNA: Sequence, topology and structure. Nucleic Acids Res. 2006;34:5402–5415. doi: 10.1093/nar/gkl655. PubMed DOI PMC

Phan A.T. Human telomeric G-quadruplex: Structures of DNA and RNA sequences. FEBS J. 2010;277:1107–1117. doi: 10.1111/j.1742-4658.2009.07464.x. PubMed DOI

Yatsunyk L.A., Mendoza O., Mergny J.L. “Nano-oddities”: Unusual nucleic acid assemblies for DNA-based nanostruc-tures and nanodevices. Acc. Chem. Res. 2014;47:1836–1844. doi: 10.1021/ar500063x. PubMed DOI

Mergny J.L., Sen D. DNA quadruple helices in nano-technology. Chem. Rev. 2019;119:6290–6325. PubMed

Huppert J.L., Balasubramanian S. Prevalence of quadruplexes in the human genome. Nucleic Acids Res. 2005;33:2908–2916. doi: 10.1093/nar/gki609. PubMed DOI PMC

Todd A.K., Johnston M., Neidle S. Highly prevalent putative quadruplex sequence motifs in human DNA. Nucleic Acids Res. 2005;33:2901–2907. doi: 10.1093/nar/gki553. PubMed DOI PMC

Lam E.Y.N., Beraldi D., Tannahill D., Balasubramanian S. G-quadruplex structures are stable and detectable in human genomic DNA. Nat. Commun. 2013;4:1796. doi: 10.1038/ncomms2792. PubMed DOI PMC

Biffi G., Tannahill D., McCafferty J., Balasubramanian S. Quantitative visualization of DNA G-quadruplex structures in human cells. Nat. Chem. 2013;5:182–186. doi: 10.1038/nchem.1548. PubMed DOI PMC

Huppert J.L., Balasubramanian S. G-quadruplexes in promoters throughout the human genome. Nucleic Acids Res. 2007;35:406–413. doi: 10.1093/nar/gkl1057. PubMed DOI PMC

Kendrick S., Hurley L.H. The role of G-quadruplex/i-motif secondary structures as cis-acting regulatory elements. Pure Appl. Chem. 2010;82:1609–1621. doi: 10.1351/PAC-CON-09-09-29. PubMed DOI PMC

Rhodes D., Lipps H.J. G-quadruplexes and their regulatory roles in biology. Nucleic Acids Res. 2015;43:8627–8637. doi: 10.1093/nar/gkv862. PubMed DOI PMC

Chambers V.S., Marsico G., Boutell J.M., Di Antonio M., Smith G.P., Balasubramanian S. High-throughput sequencing of DNA G-quadruplex structures in the human genome. Nat. Biotechnol. 2015;33:877–881. doi: 10.1038/nbt.3295. PubMed DOI

Fujioka A., Terai K., Itoh R.E., Aoki K., Nakamura T., Kuroda S., Nishida E., Matsuda M. Dynamics of the Ras/ERK MAPK cascade as monitored by fluorescent probes. J. Biol. Chem. 2006;281:8917–8926. doi: 10.1074/jbc.M509344200. PubMed DOI

Kolesnikova S., Hubálek M., Bednárová L., Cvačka J., Curtis E.A. Multimerization rules for G-quadruplexes. Nucleic Acids Res. 2017;45:8684–8696. doi: 10.1093/nar/gkx637. PubMed DOI PMC

Traut T.W. Dissociation of enzyme oligomers: A mechanism for allosteric regulation. Crit. Rev. Biochem. Mol. Biol. 1994;29:125–163. doi: 10.3109/10409239409086799. PubMed DOI

Goodsell D.S., Olson A.J. Structural symmetry and protein function. Annu. Rev. Biophys. Biomol. Struct. 2000;29:105–153. doi: 10.1146/annurev.biophys.29.1.105. PubMed DOI

Amoutzias G.D., Robertson D.L., Van de Peer Y., Oliver S.G. Choose your partners: Dimerization in eukaryotic transcription factors. Trends Biochem. Sci. 2008;33:220–229. doi: 10.1016/j.tibs.2008.02.002. PubMed DOI

Matthews J.M., Sunde M. Dimers, oligomers, everywhere. Adv. Exp. Med. Biol. 2012;747:1–18. PubMed

Watson J.D., Crick F.H.C. Molecular structure of nucleic acids: A structure for deoxyribose nucleic acid. Nature. 1953;171:737–738. doi: 10.1038/171737a0. PubMed DOI

Yakovchuk P., Protozanova E., Frank-Kamenetskii M.D. Base-stacking and base-pairing contributions into thermal stability of the DNA double helix. Nucleic Acids Res. 2006;34:564–574. doi: 10.1093/nar/gkj454. PubMed DOI PMC

Fire A., Xu S., Montgomery M.K., Kostas S.A., Driver S.E., Mello C.C. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–811. doi: 10.1038/35888. PubMed DOI

Smirnov I., Shafer R.H. Effect of loop sequence and size on DNA aptamer stability. Biochemistry. 2000;39:1462–1468. doi: 10.1021/bi9919044. PubMed DOI

Bourdoncle A., Estevez Torres A., Gosse C., Lacroix L., Vekhoff P., Le Saux T., Jullien L., Mergny J.L. Quadruplex-based molecular beacons as tunable DNA probes. J. Am. Chem. Soc. 2006;128:11094–11105. doi: 10.1021/ja0608040. PubMed DOI

Guedin A., Gros J., Alberti P., Mergny J.L. How long is too long? Effects of loop size on G-quadruplex stability. Nucleic Acids Res. 2010;38:7858–7868. doi: 10.1093/nar/gkq639. PubMed DOI PMC

Mukundan V.T., Phan A.T. Bulges in G-quadruplexes: Broadening the definition of G-quadruplex-forming sequences. J. Am. Chem. Soc. 2013;135:5017–5028. doi: 10.1021/ja310251r. PubMed DOI

Cheong C., Moore P.B. Solution structure of an unusually stable RNA tetraplex containing G- and U-quartet structures. Biochemistry. 1992;31:8406–8414. doi: 10.1021/bi00151a003. PubMed DOI

Patel P.K., Hosur R.V. NMR observation of T-tetrads in a parallel stranded DNA quadruplex formed by Saccharomyces cerevisiae telomere repeats. Nucleic Acids Res. 1999;27:2457–2464. doi: 10.1093/nar/27.12.2457. PubMed DOI PMC

Patel P.K., Bhavesh N.S., Hosur R.V. NMR observation of a novel C-tetrad in the structure of the SV40 repeat sequence GGGCGG. Biochem. Biophys. Res. Commun. 2000;270:967–971. doi: 10.1006/bbrc.2000.2479. PubMed DOI

Zhang N., Gorin A., Majumdar A., Kettani A., Chernichenko N., Skripkin E., Patel D.J. Dimeric DNA quadruplex containing major groove-aligned A-T-A-T and G-C-G-C tetrads stabilized by inter-subunit Watson-Crick A-T and G-C pairs. J. Mol. Biol. 2001;312:1073–1088. doi: 10.1006/jmbi.2001.5002. PubMed DOI

Pan B., Xiong Y., Shi K., Deng J., Sundaralingam M. Crystal structure of an RNA purine-rich tetraplex containing adenine tetrads: Implications for specific binding in RNA tetraplexes. Structure. 2003;11:815–823. doi: 10.1016/S0969-2126(03)00107-2. PubMed DOI

Kimura T., Xu Y., Komiyama M. Human telomeric RNA r(UAGGGU) sequence forms parallel tetraplex structure with U-quartet. Nucleic Acids Symp. Ser. (Oxf.) 2009;53:239–240. doi: 10.1093/nass/nrp120. PubMed DOI

Virgilio A., Esposito V., Citarella G., Mayol L., Galeone A. Structural investigations on the anti-HIV G-quadruplex-forming oligonucleotide TGGGAG and its analogues: Evidence for the presence of an A-tetrad. ChemBioChem. 2012;13:2219–2224. doi: 10.1002/cbic.201200481. PubMed DOI

Huang H., Suslov N.B., Li N.S., Shelke S.A., Evans M.E., Koldobskaya Y., Rice P.A., Piccirilli J.A. A G-quadruplex-containing RNA activates fluorescence in a GFP-like fluorophore. Nat. Chem. Biol. 2014;10:686–691. doi: 10.1038/nchembio.1561. PubMed DOI PMC

Nasiri A.H., Wurm J.P., Immer C., Weickhmann A.K., Wöhnert J. An intermolecular G-quadruplex as the basis for GTP recognition in the class V-GTP aptamer. RNA. 2016;22:1750–1759. doi: 10.1261/rna.058909.116. PubMed DOI PMC

Trachman R.J., III, Demeshkina N.A., Lau M.W.L., Panchapakesan S.S.S., Jeng S.C.Y., Unrau P.J., Ferré-D′Amaré A.R. Structural basis for high-affinity fluorophore binding and activation by RNA mango. Nat. Chem. Biol. 2017;13:807–813. doi: 10.1038/nchembio.2392. PubMed DOI PMC

Chaires J.B., Trent J.O., Gray R.D., Dean W.L., Buscaglia R., Thomas S.D., Miller D.M. An Improved model for the hTERT promoter quadruplex. PLoS ONE. 2014;9:e115580. doi: 10.1371/journal.pone.0115580. PubMed DOI PMC

Do N.Q., Lim K.W., Teo M.H., Heddi B., Phan A.T. Stacking of G-quadruplexes: NMR structure of a G-rich oligonucleotide with potential anti-HIV and anticancer activity. Nucleic Acids Res. 2011;39:9448–9457. doi: 10.1093/nar/gkr539. PubMed DOI PMC

Kato Y., Ohyama T., Mita H., Yamamoto Y. Dynamics and thermodynamics of dimerization of parallel G-quadruplexed DNA formed from d(TTAGn) (n = 3−5) J. Am. Chem. Soc. 2005;127:9980–9981. doi: 10.1021/ja050191b. PubMed DOI

Lech C.J., Heddi B., Phan A.T. Guanine base stacking in G-quadruplex nucleic acids. Nucleic Acids Res. 2013;41:2034–2046. doi: 10.1093/nar/gks1110. PubMed DOI PMC

Smargiasso N., Rosu F., Hsia W., Colson P., Baker E.S., Bowers M.T., De Pauw E., Gabelica V. G-Quadruplex DNA assemblies: Loop length, cation identity, and multimer formation. J. Am. Chem. Soc. 2008;130:10208–10216. doi: 10.1021/ja801535e. PubMed DOI

Haider S.M., Parkinson G.N., Neidle S. Molecular dynamics and principal components analysis of human telomeric quadruplex multimers. Biophys. J. 2008;95:296–311. doi: 10.1529/biophysj.107.120501. PubMed DOI PMC

Petraccone L., Trent J.O., Chaires J.B. The tail of the telomere. J. Am. Chem. Soc. 2008;130:16530–16532. doi: 10.1021/ja8075567. PubMed DOI PMC

Monchaud D., Teulade-Fichou M.P. A hitchhiker′s guide to G-quadruplex ligands. Org. Biomol. Chem. 2008;6:627–636. doi: 10.1039/B714772B. PubMed DOI

Bai L.P., Hagihara M., Jiang Z.H., Nakatani K. Ligand binding to tandem G quadruplexes from human telomeric DNA. ChemBioChem. 2008;9:2583–2587. doi: 10.1002/cbic.200800256. PubMed DOI

Haider S.M., Neidle S., Parkinson G.N. A structural analysis of G-quadruplex/ligand interactions. Biochimie. 2011;93:1239–1251. doi: 10.1016/j.biochi.2011.05.012. PubMed DOI

Zhang S., Wu Y., Zhang W. G-quadruplex structures and their interaction diversity with ligands. ChemMedChem. 2014;9:899–911. doi: 10.1002/cmdc.201300566. PubMed DOI

Hu M.H., Chen S.B., Wang B., Ou T.M., Gu L.Q., Tan J.H., Huang Z.S. Specific targeting of telomeric multimeric G-quadruplexes by a new triaryl-substituted imidazole. Nucleic Acids Res. 2017;45:1606–1618. doi: 10.1093/nar/gkw1195. PubMed DOI PMC

Funke A., Karg B., Dickerhoff J., Balke D., Müller S., Weisz K. Ligand- induced dimerization of a truncated parallel MYC G-Quadruplex. ChemBioChem. 2018;19:505–512. doi: 10.1002/cbic.201700593. PubMed DOI

Krishnan-Ghosh Y., Liu D., Balasubramanian S. Formation of an interlocked quadruplex dimer by d(GGGT) J. Am. Chem. Soc. 2004;126:11009–11016. doi: 10.1021/ja049259y. PubMed DOI

Sen D., Gilbert W. Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis. Nature. 1988;334:65–70. doi: 10.1038/334364a0. PubMed DOI

Sundquist W.I., Klug A. Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops. Nature. 1989;342:825–829. doi: 10.1038/342825a0. PubMed DOI

Williamson J.R., Raghuraman M.K., Cech T.R. Monovalent cation-induced structure of telomeric DNA: The G-quartet model. Cell. 1989;59:871–880. doi: 10.1016/0092-8674(89)90610-7. PubMed DOI

Sen D., Gilbert W. Novel DNA superstructures formed by telomere-like oligomers. Biochemistry. 1992;31:65–70. doi: 10.1021/bi00116a011. PubMed DOI

Laughlan G., Murchie A.I., Norman D.G., Moore M.H., Moody P.C., Lilley D.M., Luisi B. The high-resolution crystal structure of a parallel-stranded guanine tetraplex. Science. 1994;265:520–524. doi: 10.1126/science.8036494. PubMed DOI

Phillips K., Dauter Z., Murchie A.I., Lilley D.M., Luisi B. The crystal structure of a parallel-stranded guanine tetraplex at 0.95 A resolution. J. Mol. Biol. 1997;273:171–182. doi: 10.1006/jmbi.1997.1292. PubMed DOI

Borbone N., Amato J., Oliviero G., D′Atri V., Gabelica V., De Pauw E., Piccialli G., Mayol L. d(CGGTGGT) forms an octameric parallel G-quadruplex via stacking of unusual G(:C):G(:C):G(:C):G(:C) octads. Nucleic Acids Res. 2011;39:7848–7857. doi: 10.1093/nar/gkr489. PubMed DOI PMC

D′Atri V., Borbone N., Amato J., Gabelica V., D′Errico S., Piccialli G., Mayol L., Oliviero G. DNA-based nanostructures: The effect of the base sequence on octamer formation from d(XGGYGGT) tetramolecular G-quadruplexes. Biochimie. 2014;99:119–128. doi: 10.1016/j.biochi.2013.11.020. PubMed DOI

Kuryavyi V., Cahoon L.A., Seifert H.S., Patel D.J. RecA-binding pilE G4 sequence essential for pilin antigenic variation forms monomeric and 5′ end-stacked dimeric parallel G-quadruplexes. Structure. 2012;20:2090–2102. doi: 10.1016/j.str.2012.09.013. PubMed DOI PMC

Adrian M., Ang D.J., Lech C.J., Heddi B., Nicolas A., Phan A.T. Structure and conformational dynamics of a stacked dimeric G-quadruplex formed by the human CEB1 minisatellite. J. Am. Chem. Soc. 2014;136:6297–6305. doi: 10.1021/ja4125274. PubMed DOI

Matsugami A., Ouhashi K., Kanagawa M., Liu H., Kanagawa S., Uesugi S., Katahira M. An intramolecular quadruplex of (GGA) (4) triplet repeat DNA with a G:G:G:G tetrad and a G(:A):G(:A):G(:A):G heptad, and its dimeric interaction. J. Mol. Biol. 2001;313:255–269. doi: 10.1006/jmbi.2001.5047. PubMed DOI

Kuryavyi V., Phan A.T., Patel D.J. Solution structures of all parallel-stranded monomeric and dimeric G-quadruplex scaffolds of the human c-kit2 promoter. Nucleic Acids Res. 2010;38:6757–6773. doi: 10.1093/nar/gkq558. PubMed DOI PMC

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. J. Am. Chem. Soc. 2012;134:4132–4141. doi: 10.1021/ja208483v. PubMed DOI

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. J. Am. Chem. Soc. 2013;135:19319–19329. doi: 10.1021/ja4101358. PubMed DOI

Chen Y., Yang D. Sequence, stability, and structure of G-quadruplexes and their interactions with drugs. Curr. Protoc. Nucleic Acid Chem. 2012;50:1–17. PubMed PMC

Yaku H., Murashima T., Tateishi-Karimata H., Nakano S., Miyoshi D., Sugimoto N. Study on effects of molecular crowding on G-quadruplex-ligand binding and ligand-mediated telomerase inhibition. Methods. 2013;64:19–27. doi: 10.1016/j.ymeth.2013.03.028. PubMed DOI

Bhattacharyya D., Mirihana Arachchilage G., Basu S. Metal cations in G- quadruplex folding and stability. Front. Chem. 2016;4:38. doi: 10.3389/fchem.2016.00038. PubMed DOI PMC

Kar A., Jones N., Arat N.Ö., Fishel R., Griffith J.D. Long repeating (TTAGGG)n single-stranded DNA self-condenses into compact beaded filaments stabilized by G-quadruplex formation. J. Biol. Chem. 2018;293:9473–9485. doi: 10.1074/jbc.RA118.002158. PubMed DOI PMC

Podbevsek P., Plavec J. KRAS promoter oligonucleotide with decoy activity dimerizes into a unique topology consisting of two G-quadruplex units. Nucleic Acids Res. 2016;44:917–925. doi: 10.1093/nar/gkv1359. PubMed DOI PMC

Marsh T.C., Henderson E. G-wires: Self-assembly of a telomeric oligonucleotide, d(GGGGTTGGGG), into large superstructures. Biochemistry. 1994;33:10718–10724. doi: 10.1021/bi00201a020. PubMed DOI

Bose K., Lech C.J., Heddi B., Phan A.T. High-resolution AFM structure of DNA G-wires in aqueous solution. Nat. Commun. 2018;9:1959. doi: 10.1038/s41467-018-04016-y. PubMed DOI PMC

Hessari N.M., Spindler L., Troha T., Lam W.C., Drevensek-Olenik I., da Silva M.W. Programmed self-assembly of a quadruplex DNA nanowire. Chemistry. 2014;20:3626–3630. doi: 10.1002/chem.201300692. PubMed DOI

Guo X., Liu S., Yu Z. Bimolecular quadruplexes and their transitions to higher-order molecular structures detected by ESI-FTICR-MS. J. Am. Soc. Mass Spectrom. 2007;18:1467–1476. doi: 10.1016/j.jasms.2007.05.003. PubMed DOI

Majerová T., Streckerová T., Bednárová L., Curtis E.A. Sequence requirements of intrinsically fluorescent G-quadruplexes. Biochemistry. 2018;57:4052–4062. doi: 10.1021/acs.biochem.8b00252. PubMed DOI

Kolesnikova S., Srb P., Vrzal L., Lawrence M., Veverka V., Curtis E.A. GTP-dependent formation of multimeric G-quadruplexes. ACS Chem. Biol. doi: 10.1021/acschembio.9b00428. in press. PubMed DOI

Švehlová K., Lawrence M.S., Bednárová L., Curtis E.A. Altered biochemical specificity of G-quadruplexes with mutated tetrads. Nucleic Acids Res. 2016;44:10789–10803. doi: 10.1093/nar/gkw987. PubMed DOI PMC

Lu M., Guo Q., Kallenbach N.R. Structure and stability of sodium and potassium complexes of dT4G4 and dT4G4T. Biochemistry. 1992;31:2455–2459. doi: 10.1021/bi00124a003. PubMed DOI

Creze C., Rinaldi B., Haser R., Bouvet P., Gouet P. Structure of a d(TGGGGT) quadruplex crystallized in the presence of Li+ ions. Acta Crystallogr. D Biol. Crystallogr. 2007;63:682–688. doi: 10.1107/S0907444907013315. PubMed DOI

Deng J., Xiong Y., Sundaralingam M. X-ray analysis of an RNA tetraplex (UGGGGU)(4) with divalent Sr(2+) ions at subatomic resolution (0.61 A) Proc. Nat. Acad. Sci. USA. 2001;98:13665–13670. doi: 10.1073/pnas.241374798. PubMed DOI PMC

Hazel P., Huppert J., Balasubramanian S., Neidle S. Loop-length-dependent folding of G-quadruplexes. J. Am. Chem. Soc. 2004;126:16405–16415. doi: 10.1021/ja045154j. PubMed DOI

Risitano A., Fox K.R. Stability of intramolecular DNA quadruplexes: Comparison with DNA duplexes. Biochemistry. 2003;42:6507–6513. doi: 10.1021/bi026997v. PubMed DOI

Blackburn E.H., Gall J.G. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J. Mol. Biol. 1978;120:33–53. doi: 10.1016/0022-2836(78)90294-2. PubMed DOI

Jacob N.K., Skopp R., Price C.M. G-overhang dynamics at Tetrahymena telomeres. EMBO J. 2001;20:4299–4308. doi: 10.1093/emboj/20.15.4299. PubMed DOI PMC

Moyzis R.K., Buckingham J.M., Cram L.S., Dani M., Deaven L.L., Jones M.D., Meyne J., Ratliff R.L., Wu J.R. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc. Nat. Acad. Sci. USA. 1988;85:6622–6626. doi: 10.1073/pnas.85.18.6622. PubMed DOI PMC

Wright W.E., Tesmer V.M., Huffman K.E., Levene S.D., Shay J.W. Normal human chromosomes have long G-rich telomeric overhangs at one end. Genes Dev. 1997;11:2801–2809. doi: 10.1101/gad.11.21.2801. PubMed DOI PMC

Henderson E., Hardin C.C., Walk S.K., Tinoco I., Jr., Blackburn E.H. Telomeric DNA oligonucleotides form novel intramolecular structures containing guanine- guanine base pairs. Cell. 1987;51:899–908. doi: 10.1016/0092-8674(87)90577-0. PubMed DOI

Neidle S., Parkinson G.N. The structure of telomeric DNA. Curr. Opin. Struct. Biol. 2003;13:275–283. doi: 10.1016/S0959-440X(03)00072-1. PubMed DOI

Li J., Correia J.J., Wang L., Trent J.O., Chaires J.B. Not so crystal clear: The structure of the human telomere G-quadruplex in solution differs from that present in a crystal. Nucleic Acids Res. 2005;33:4649–4659. doi: 10.1093/nar/gki782. PubMed DOI PMC

Petraccone L. Higher-order quadruplex structures. Top. Curr. Chem. 2013;330:23–46. PubMed

Yu H.Q., Miyoshi D., Sugimoto N. Characterization of structure and stability of long telomeric DNA G-quadruplexes. J. Am. Chem. Soc. 2006;128:15461–15468. doi: 10.1021/ja064536h. PubMed DOI

Kankia B. Tetrahelical monomolecular architecture of DNA: A new building block for nanotechnology. J. Phys. Chem. B. 2014;118:6134–6140. doi: 10.1021/jp503276q. PubMed DOI

Kankia B. Monomolecular tetrahelix of polyguanine with a strictly defined folding pattern. Sci. Rep. 2018;8:10115. doi: 10.1038/s41598-018-28572-x. PubMed DOI PMC

Xu Y., Komiyama M. The structural studies of human telomeric DNA using AFM. Nucleic Acids Symp. Ser. (Oxf). 2007;51:241–242. doi: 10.1093/nass/nrm121. PubMed DOI

Xu X., Ishizuka T., Kurabayashi K., Komiyama M. Consecutive formation of G-quadruplexes in human telomeric-overhang DNA: A protective capping structure for telomere ends. Angew. Chem. Int. Ed. 2009;48:7833–7836. doi: 10.1002/anie.200903858. PubMed DOI

Petraccone L., Spink C., Trent J.O., Garbett N.C., Mekmaysy C.S., Giancola C., Chaires J.B. Structure and stability of higher-order human telomeric quadruplexes. J. Am. Chem. Soc. 2011;133:20951–20961. doi: 10.1021/ja209192a. PubMed DOI PMC

Schaffitzel C., Berger I., Postberg J., Hanes J., Lipps H.J., Pluckthun A. In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei. Proc. Nat. Acad. Sci. USA. 2001;98:8572–8577. doi: 10.1073/pnas.141229498. PubMed DOI PMC

Moye A.L., Porter K.C., Cohen S.B., Phan T., Zyner K.G., Sasaki N., Lovrecz G.O., Beck J.L., Bryan T.M. Telomeric G-quadruplexes are a substrate and site of localization for human telomerase. Nat. Commun. 2015;6:7643. doi: 10.1038/ncomms8643. PubMed DOI PMC

Zhao C., Wu L., Ren J., Xu Y., Qu X. Targeting human telomeric higher-order DNA: Dimeric G-quadruplex units serve as preferred binding site. J. Am. Chem. Soc. 2013;135:18786–18789. doi: 10.1021/ja410723r. PubMed DOI

Huang X.X., Zhu L.N., Wu B., Huo Y.F., Duan N.N., Kong D.M. Two cationic porphyrin isomers showing different multimeric G-quadruplex recognition specificity against monomeric G-quadruplexes. Nucleic Acids Res. 2014;42:8719–8731. doi: 10.1093/nar/gku526. PubMed DOI PMC

Zhang Q., Liu Y.C., Kong D.M., Guo D.S. Tetraphenylethene derivatives with different numbers of positively charged side arms have different multimeric G- quadruplex recognition specificity. Chemistry. 2015;21:13253–13260. doi: 10.1002/chem.201501847. PubMed DOI

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. J. Am. Chem. Soc. 2006;128:1096–1098. doi: 10.1021/ja055636a. PubMed DOI PMC

González V., Hurley L.H. The c-MYC NHE III1: Function and regulation. Annu. Rev. Pharmacol. Toxicol. 2008;50:111–129. doi: 10.1146/annurev.pharmtox.48.113006.094649. PubMed DOI

Mathad R.I., Hatzakis E., Dai J., Yang D. c-MYC promoter G-quadruplex formed at the 5′-end of NHE III1 element: Insights into biological relevance and parallel-stranded G-quadruplex stability. Nucleic Acids Res. 2011;39:9023–9033. doi: 10.1093/nar/gkr612. PubMed DOI PMC

Kerkour A., Marquevielle J., Ivashchenko S., Yatsunyk L.A., Mergny J.L., Salgado G.F. High-resolution three-dimensional NMR structure of the KRAS proto-oncogene promoter reveals key features of a G-quadruplex involved in transcriptional regulation. J. Biol. Chem. 2017;292:8082–8091. doi: 10.1074/jbc.M117.781906. PubMed DOI PMC

Matsugami A., Okuizumi T., Uesugi S., Katahira M. Intramolecular higher order packing of parallel quadruplexes comprising a G:G:G:G tetrad and a G(:A):G(:A):G(:A):G heptad of GGA triplet repeat DNA. J. Biol. Chem. 2003;278:28147–28153. doi: 10.1074/jbc.M303694200. PubMed DOI

Palumbo S.L., Memmott R.M., Uribe D.J., Krotova-Khan Y., Hurley J.H., Ebbinghaus S.W. A novel G-quadruplex-forming GGA repeat region in the c-myb promoter is a critical regulator of promoter activity. Nucleic Acids Res. 2008;36:1755–1769. doi: 10.1093/nar/gkm1069. PubMed DOI PMC

Broxson C., Beckett J., Tornaletti S. Transcription arrest by a G-quadruplex forming-trinucleotide repeat sequence from the human c-myb gene. Biochemistry. 2011;50:4162–4172. doi: 10.1021/bi2002136. PubMed DOI

Hirsch M.R., Gaugler L., Deagostini-Bazin H., Bally-Cuif L., Goridis C. Identification of positive and negative regulatory elements governing cell-type-specific expression of the neural cell adhesion molecule gene. Mol. Cell. Biol. 1990;10:1959–1968. doi: 10.1128/MCB.10.5.1959. PubMed DOI PMC

Chamboredon S., Briggs J., Vial E., Hurault J., Galvagni F., Oliviero S., Bos T., Castellazzi M. v-Jun downregulates the SPARC target gene by binding to the proximal promoter indirectly through Sp1/3. Oncogene. 2003;22:4047–4061. doi: 10.1038/sj.onc.1206713. PubMed DOI

Morgan R.K., Batra H., Gaerig V.C., Hockings J., Brooks T.A. Identification and characterization of a new G-quadruplex forming region within the kRAS promoter as a transcriptional regulator. Biochim. Biophys. Acta. 2016;1859:235–245. doi: 10.1016/j.bbagrm.2015.11.004. PubMed DOI

Islam I., Baba Y., Witarto A.B., Yoshida W. G-quadruplex-forming GGA repeat region functions as a negative regulator of the Ccnb1ip1 enhancer. Biosci. Biotechnol. Biochem. 2019;7:1–6. doi: 10.1080/09168451.2019.1611412. PubMed DOI

Palumbo S.L., Ebbinghaus S.W., Hurley L.H. Formation of a unique end-to-end stacked pair of G-quadruplexes in the hTERT core promoter with implications for inhibition of telomerase by G-quadruplex-interactive ligands. J. Am. Chem. Soc. 2009;131:10878–10891. doi: 10.1021/ja902281d. PubMed DOI PMC

Kang H.J., Cui Y., Yin H., Scheid A., Hendricks W.P.D., Schmidt J., Sekulic A., Kong D., Trent J.M., Gokhale V., et al. A pharmacological chaperone molecule induces cancer cell death by restoring tertiary DNA structures in mutant hTERT promoters. J. Am. Chem. Soc. 2016;138:13673–13692. doi: 10.1021/jacs.6b07598. PubMed DOI

Micheli E., Martufi M., Cacchione S., De Santis P., Savino M. Self-organization of G-quadruplex structures in the hTERT core promoter stabilized by polyaminic side chain perylene derivatives. Biophys. Chem. 2010;153:43–53. doi: 10.1016/j.bpc.2010.10.003. PubMed DOI

Saha D., Singh A., Hussain T., Srivastava V., Sengupta S., Kar A., Dhapola P., Dhople V., Ummanni R., Chowdhury S. Epigenetic suppression of human telomerase (hTERT) is mediated by the metastasis suppressor NME2 in a G-quadruplex-dependent fashion. J. Biol. Chem. 2017;292:15205–15215. doi: 10.1074/jbc.M117.792077. PubMed DOI PMC

Yafe A., Etzioni S., Weisman-Shomer P., Fry M. Formation and properties of hairpin and tetraplex structures of guanine-rich regulatory sequences of muscle-specific genes. Nucleic Acids Res. 2005;33:2887–2900. doi: 10.1093/nar/gki606. PubMed DOI PMC

Rigo R., Sissi C. Characterization of G4-G4 crosstalk in the c-KIT promoter region. Biochemistry. 2017;56:4309–4312. doi: 10.1021/acs.biochem.7b00660. PubMed DOI

Ducani C., Bernardinelli G., Högberg B., Keppler B.K., Terenzi A. Interplay of three G-quadruplex units in the KIT promoter. J. Am. Chem. Soc. 2019;141:10205–10213. doi: 10.1021/jacs.8b12753. PubMed DOI

Lavezzo E., Berselli M., Frasson I., Perrone R., Palù G., Brazzale A.R., Richter S.N., Toppo S. G-quadruplex forming sequences in the genome of all known viruses: A comprehensive guide. PLoS Comput. Biol. 2018;14:e1006675. doi: 10.1371/journal.pcbi.1006675. PubMed DOI PMC

Frasson I., Nadai M., Richter S.N. Conserved G-quadruplexes regulate the immediate early promoters of human Alphaherpesviruses. Molecules. 2019;24:2375. doi: 10.3390/molecules24132375. PubMed DOI PMC

Xu Y., Kimura T., Komiyama M. Human telomere RNA and DNA form an intermolecular G-quadruplex. Nucleic Acids Symp. Ser. (Oxf.) 2008;52:169–170. doi: 10.1093/nass/nrn086. PubMed DOI

Wanrooij P.H., Uhler J.P., Shi Y., Westerlund F., Falkenberg M., Gustafsson C.M. A hybrid G-quadruplex structure formed between RNA and DNA explains the extraordinary stability of the mitochondrial R-loop. Nucleic Acids Res. 2012;40:10334–10344. doi: 10.1093/nar/gks802. PubMed DOI PMC

Zheng K.W., Wu R.Y., He Y.D., Xiao S., Zhang J.Y., Liu J.Q., Hao Y.H., Tan Z. A competitive formation of DNA:RNA hybrid G-quadruplex is responsible to the mitochondrial transcription termination at the DNA replication priming site. Nucleic Acids Res. 2014;42:10832–10844. doi: 10.1093/nar/gku764. PubMed DOI PMC

Zheng K.W., Xiao S., Liu J.Q., Zhang J.Y., Hao Y.H., Tan Z. Co-transcriptional formation of DNA:RNA hybrid G-quadruplex and potential function as constitutional cis element for transcription control. Nucleic Acids Res. 2013;41:5533–5541. doi: 10.1093/nar/gkt264. PubMed DOI PMC

Xiao S., Zhang J.Y., Wu J., Wu R.Y., Xia Y., Zheng K.W., Hao Y.H., Zhou X., Tan Z. Formation of DNA:RNA hybrid G-quadruplexes of two G-quartet layers in transcription: Expansion of the prevalence and diversity of G-quadruplexes in genomes. Angew. Chem. Int. Ed. Engl. 2014;53:13110–13114. doi: 10.1002/anie.201407045. PubMed DOI

Xiao S., Zhang J.Y., Zheng K.W., Hao Y.H., Tan Z. Bioinformatic analysis reveals an evolutional selection for DNA:RNA hybrid G-quadruplex structures as putative transcription regulatory elements in warm-blooded animals. Nucleic Acids Res. 2013;41:10379–10390. doi: 10.1093/nar/gkt781. PubMed DOI PMC

Zhang J.Y., Zheng K.W., Xiao S., Hao Y.H., Tan Z. Mechanism and manipulation of DNA:RNA hybrid G-quadruplex formation in transcription of G-rich DNA. J. Am. Chem. Soc. 2014;136:1381–1390. doi: 10.1021/ja4085572. PubMed DOI

Zhao Y., Zhang J.Y., Zhang Z.Y., Tong T.J., Hao Y.H., Tan Z. Real-time detection reveals responsive cotranscriptional formation of persistent intramolecular DNA and intermolecular DNA:RNA hybrid G-quadruplexes stabilized by R-loop. Anal. Chem. 2017;89:6036–6042. doi: 10.1021/acs.analchem.7b00625. PubMed DOI

Shrestha P., Xiao S., Dhakal S., Tan Z., Mao H. Nascent RNA transcripts facilitate the formation of G-quadruplexes. Nucleic Acids Res. 2014;42:7236–7246. doi: 10.1093/nar/gku416. PubMed DOI PMC

Curtis E.A., Liu D.R. Discovery of widespread GTP-binding motifs in genomic RNA and DNA. Chem. Biol. 2013;20:521–532. doi: 10.1016/j.chembiol.2013.02.015. PubMed DOI PMC

Mechanical Stability and Unfolding Pathways of Parallel Tetrameric G-Quadruplexes Probed by Pulling Simulations

The presence of a G-quadruplex prone sequence upstream of a minimal promoter increases transcriptional activity in the yeast Saccharomyces cerevisiae

G-quadruplexes in helminth parasites

Quadruplex-Forming Motif Inserted into 3'UTR of Ty1his3-AI Retrotransposon Inhibits Retrotransposition in Yeast

Overlapping but distinct: a new model for G-quadruplex biochemical specificity

Diversity of Parallel Guanine Quadruplexes Induced by Guanine Substitutions

In-Depth Bioinformatic Analyses of Nidovirales Including Human SARS-CoV-2, SARS-CoV, MERS-CoV Viruses Suggest Important Roles of Non-canonical Nucleic Acid Structures in Their Lifecycles