DNA quadruplex structures provide an additional layer of regulatory control in genome maintenance and gene expression and are widely used in nanotechnology. We report the discovery of an unprecedented tetrastranded structure formed from a native G-rich DNA sequence originating from the telomeric region of Caenorhabditis elegans. The structure is defined by multiple properties that distinguish it from all other known DNA quadruplexes. Most notably, the formation of a stable so-called KNa-quadruplex (KNaQ) requires concurrent coordination of K+ and Na+ ions at two distinct binding sites. This structure provides novel insight into G-rich DNA folding under ionic conditions relevant to eukaryotic cell physiology and the structural evolution of telomeric DNA. It highlights the differences between the structural organization of human and nematode telomeric DNA, which should be considered when using C. elegans as a model in telomere biology, particularly in drug screening applications. Additionally, the absence/presence of KNaQ motifs in the host/parasite introduces an intriguing possibility of exploiting the KNaQ fold as a plausible antiparasitic drug target. The structure's unique shape and ion dependency and the possibility of controlling its folding by using low-molecular-weight ligands can be used for the design or discovery of novel recognition DNA elements and sensors.

Central European Institute of Technology Masaryk University Kamenice 753 5 62500 Brno Czech Republic

Current address Center for Molecular Medicine Cologne University of Cologne 50931 Cologne Germany

Faculty of Chemistry Brno University of Technology Purkynova 464 61200 Brno Czech Republic

Institute of Biophysics Czech Academy of Sciences Kralovopolska 135 61265 Brno Czech Republic

Laboratoire d'Optique et Biosciences Ecole Polytechnique CNRS Inserm Institut Polytechnique de Paris 91120 Palaiseau France

Slovenian NMR Centre National Institute of Chemistry Hajdrihova 19 1000 Ljubljana Slovenia

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R. J. Wellinger, D. Sen, Eur. J. Cancer 1997, 33, 735-749.

V. Brázda, M. Bartas, R. P. Bowater, Trends Genet. 2021, 37, 730-744.

T. M. Bryan, Molecules 2020, 25, 3686;

S. Asamitsu, N. Shioda, H. Sugiyama, in Annual Reports in Medicinal Chemistry, Elsevier, Amsterdam, 2020, pp. 77-99;

N. Kosiol, S. Juranek, P. Brossart, A. Heine, K. Paeschke, Mol. Cancer 2021, 20, 40.

Y. Wang, D. J. Patel, Structure 1993, 1, 263-282;

G. N. Parkinson, M. P. H. Lee, S. Neidle, Nature 2002, 417, 876-880;

J. Dai, C. Punchihewa, A. Ambrus, D. Chen, R. A. Jones, D. Yang, Nucleic Acids Res. 2007, 35, 2440-2450;

J. Dai, M. Carver, C. Punchihewa, R. A. Jones, D. Yang, Nucleic Acids Res. 2007, 35, 4927-4940;

A. T. Phan, V. Kuryavyi, K. N. Luu, D. J. Patel, Nucleic Acids Res. 2007, 35, 6517-6525;

K. W. Lim, S. Amrane, S. Bouaziz, W. Xu, Y. Mu, D. J. Patel, K. N. Luu, A. T. Phan, J. Am. Chem. Soc. 2009, 131, 4301-4309;

B. Heddi, A. T. Phan, J. Am. Chem. Soc. 2011, 133, 9824-9833;

K. W. Lim, V. C. M. Ng, N. Martín-Pintado, B. Heddi, A. T. Phan, Nucleic Acids Res. 2013, 41, 10556-10562;

P. Galer, B. Wang, P. Šket, J. Plavec, Angew. Chem. Int. Ed. 2016, 55, 1993-1997;

C. Lin, D. Yang, in Telomeres and Telomerase (Ed.: Z. Songyang), Springer New York, New York, 2017, pp. 171-196;

C. Liu, B. Zhou, Y. Geng, D. Y. Tam, R. Feng, H. Miao, N. Xu, X. Shi, Y. You, Y. Hong, B. Z. Tang, P. K. Lo, V. Kuryavyi, G. Zhu, Chem. Sci. 2019, 10, 218-226.

E. Henderson, C. C. Hardin, S. K. Walk, I. Tinoco, E. H. Blackburn, Cell 1987, 51, 899-908;

A. T. Phan, FEBS J. 2010, 277, 1107-1117;

P. L. T. Tran, J.-L. Mergny, P. Alberti, Nucleic Acids Res. 2011, 39, 3282-3294;

P. Školáková, S. Foldynová-Trantírková, K. Bednářová, R. Fiala, M. Vorlíčková, L. Trantírek, Nucleic Acids Res. 2015, 43, 4733-4745;

W.-Q. Wu, M.-L. Zhang, C.-P. Song, J. Biol. Chem. 2020, 295, 5461-5469.

M. Gajarský, M. L. Živković, P. Stadlbauer, B. Pagano, R. Fiala, J. Amato, L. Tomáška, J. Šponer, J. Plavec, L. Trantírek, J. Am. Chem. Soc. 2017, 139, 3591-3594.

J. Marquevielle, A. De Rache, B. Vialet, E. Morvan, J.-L. Mergny, S. Amrane, Nucleic Acids Res. 2022, 50, 7134-7146.

D. H. Lackner, J. Karlseder, Worm 2013, 2, e21073.

M. Adrian, B. Heddi, A. T. Phan, Methods 2012, 57, 11-24.

P. Schultze, R. F. Macaya, J. Feigon, J. Mol. Biol. 1994, 235, 1532-1547;

K. W. Lim, P. Alberti, A. Guédin, L. Lacroix, J.-F. Riou, N. J. Royle, J.-L. Mergny, A. T. Phan, Nucleic Acids Res. 2009, 37, 6239-6248.

R. Tippana, W. Xiao, S. Myong, Nucleic Acids Res. 2014, 42, 8106-8114;

J. Jana, Y. M. Vianney, N. Schröder, K. Weisz, Nucleic Acids Res. 2022, 50, 7161-7175.

N. Zhang, A. Gorin, A. Majumdar, A. Kettani, N. Chernichenko, E. Skripkin, D. J. Patel, J. Mol. Biol. 2001, 312, 1073-1088;

N. Escaja, B. Mir, M. Garavís, C. González, Molecules 2022, 27, 5287.

A. Kettani, S. Bouaziz, A. Gorin, H. Zhao, R. A. Jones, D. J. Patel, J. Mol. Biol. 1998, 282, 619-636.

S. Bouaziz, A. Kettani, D. J. Patel, J. Mol. Biol. 1998, 282, 637-652.

P. Šket, M. Črnugelj, J. Plavec, Nucleic Acids Res. 2005, 33, 3691-3697;

Z.-F. Wang, M.-H. Li, S.-T. D. Hsu, T.-C. Chang, Nucleic Acids Res. 2014, 42, 4723-4733.

V. Pirota, M. Stasi, A. Benassi, F. Doria, in Annual Reports in Medicinal Chemistry (Ed.: S. Neidle), Academic Press, New York, 2020, pp. 163-196.

A. Ghosh, M. Trajkovski, M.-P. Teulade-Fichou, V. Gabelica, J. Plavec, Angew. Chem. Int. Ed. 2022, 61, e202207384.

A. Renaud de la Faverie, A. Guédin, A. Bedrat, L. A. Yatsunyk, J.-L. Mergny, Nucleic Acids Res. 2014, 42, e65.

V. I. Stsiapura, A. A. Maskevich, V. A. Kuzmitsky, V. N. Uversky, I. M. Kuznetsova, K. K. Turoverov, J. Phys. Chem. B 2008, 112, 15893-15902.

J. Bethony, S. Brooker, M. Albonico, S. M. Geiger, A. Loukas, D. Diemert, P. J. Hotez, Lancet 2006, 367, 1521-1532.

V. Brázda, J. Kolomazník, J. Lýsek, M. Bartas, M. Fojta, J. Šťastný, J.-L. Mergny, Bioinformatics 2019, 35, 3493-3495.

V. Kocman, J. Plavec, Nat. Commun. 2014, 5, 5831;

V. Kocman, J. Plavec, Nat. Commun. 2017, 8, 15355;

M. L. Živković, M. Gajarský, K. Beková, P. Stadlbauer, L. Vicherek, M. Petrová, R. Fiala, I. Rosenberg, J. Šponer, J. Plavec, L. Trantírek, Nucleic Acids Res. 2021, 49, 2317-2332;

S. Roschdi, J. Yan, Y. Nomura, C. A. Escobar, R. J. Petersen, C. A. Bingman, M. Tonelli, R. Vivek, E. J. Montemayor, M. Wickens, S. G. Kennedy, S. E. Butcher, Nat. Struct. Mol. Biol. 2022, 29, 1113-1121.

R. Hänsel, F. Löhr, L. Trantirek, V. Dötsch, J. Am. Chem. Soc. 2013, 135, 2816-2824.

K. Jurikova, M. Gajarsky, M. Hajikazemi, J. Nosek, K. Prochazkova, K. Paeschke, L. Trantirek, L. Tomaska, J. Biol. Chem. 2020, 295, 8958-8971.

M. W. Gray, J. Lukes, J. M. Archibald, P. J. Keeling, W. F. Doolittle, Science 2010, 330, 920-921.

W. Lee, M. Tonelli, J. L. Markley, Bioinformatics 2015, 31, 1325-1327.

R. Galindo-Murillo, J. C. Robertson, M. Zgarbová, J. Šponer, M. Otyepka, P. Jurečka, T. E. I. Cheatham, J. Chem. Theory Comput. 2016, 12, 4114-4127.

D. A. Case, K. Belfon, I. Y. Ben-Shalom, S. R. Brozell, D. S. Cerutti, T. E. Cheatham III, V. W. D. Cruzeiro, T. A. Darden, R. E. Duke, G. Giambasu, M. K. Gilson, H. Gohlke, A. W. Goetz, R. Harris, S. Izadi, S. A. Izmailov, K. Kasavajhala, A. Kovalenko, R. Krasny, T. Kurtzman, T. S. Lee, S. LeGrand, P. Li, C. Lin, J. Liu, T. Luchko, R. Luo, V. Man, K. M. Merz, Y. Miao, O. Mikhailovskii, G. Monard, H. Nguyen, A. Onufriev, F. Pan, S. Pantano, R. Qi, D. R. Roe, A. Roitberg, C. Sagui, S. Schott-Verdugo, J. Shen, C. L. Simmerling, N. R. Skrynnikov, J. Smith, J. Swails, R. C. Walker, J. Wang, L. Wilson, R. M. Wolf, X. Wu, Y. Xiong, Y. Xue, D. M. York, P. A. Kollman, AMBER 20, University of California, San Francisco, 2020.

E. F. Pettersen, T. D. Goddard, C. C. Huang, G. S. Couch, D. M. Greenblatt, E. C. Meng, T. E. Ferrin, J. Comput. Chem. 2004, 25, 1605-1612.

M. Zgarbová, J. Šponer, M. Otyepka, T. E. Cheatham, R. Galindo-Murillo, P. Jurečka, J. Chem. Theory Comput. 2015, 11, 5723-5736.

M. Zgarbová, F. J. Luque, J. Šponer, T. E. Cheatham, M. Otyepka, P. Jurečka, J. Chem. Theory Comput. 2013, 9, 2339-2354;

A. Pérez, I. Marchán, D. Svozil, J. Sponer, T. E. Cheatham, C. A. Laughton, M. Orozco, Biophys. J. 2007, 92, 3817-3829.

M. Krepl, M. Zgarbová, P. Stadlbauer, M. Otyepka, P. Banáš, J. Koča, T. E. Cheatham, P. Jurečka, J. Sponer, J. Chem. Theory Comput. 2012, 8, 2506-2520.

W. D. Cornell, P. Cieplak, C. I. Bayly, I. R. Gould, K. M. Merz, D. M. Ferguson, D. C. Spellmeyer, T. Fox, J. W. Caldwell, P. A. Kollman, J. Am. Chem. Soc. 1995, 117, 5179-5197.

H. J. C. Berendsen, J. R. Grigera, T. P. Straatsma, J. Phys. Chem. 1987, 91, 6269-6271.

I. S. Joung, T. E. Cheatham, J. Phys. Chem. B 2008, 112, 9020-9041.

D. A. Case, T. A. Darden, T. E. Cheatham III, C. L. Simmerling, J. Wang, R. E. Duke, R. Luo, R. C. Walker, W. Zhang, K. M. Merz, B. Roberts, S. Hayik, A. Roitberg, G. Seabra, J. Swails, A. W. Götz, I. Kolossváry, K. F. Wong, F. Paesani, J. Vanicek, R. M. Wolf, J. Liu, X. Wu, S. R. Brozell, T. Steinbrecher, H. Gohlke, Q. Cai, X. Ye, J. Wang, M.-J. Hsieh, G. Cui, D. R. Roe, D. H. Mathews, M. G. Seetin, R. Salomon-Ferrer, C. Sagui, V. Babin, T. Luchko, S. Gusarov, A. Kovalenko, P. A. Kollman, AMBER 12, University of California, San Francisco, 2012.

P. Stadlbauer, B. Islam, M. Otyepka, J. Chen, D. Monchaud, J. Zhou, J.-L. Mergny, J. Šponer, J. Chem. Theory Comput. 2021, 17, 1883-1899.

R. Salomon-Ferrer, A. W. Götz, D. Poole, S. Le Grand, R. C. Walker, J. Chem. Theory Comput. 2013, 9, 3878-3888;

D. A. Case, I. Y. Ben-Shalom, S. R. Brozell, D. S. Cerutti, T. E. Cheatham III, V. W. D. Cruzeiro, T. A. Darden, R. E. Duke, D. Ghoreishi, M. K. Gilson, H. Gohlke, A. W. Goetz, D. Greene, R Harris, N. Homeyer, Y. Huang, S. Izadi, A. Kovalenko, T. Kurtzman, T. S. Lee, S. LeGrand, P. Li, C. Lin, J. Liu, T. Luchko, R. Luo, D. J. Mermelstein, K. M. Merz, Y. Miao, G. Monard, C. Nguyen, H. Nguyen, I. Omelyan, A. Onufriev, F. Pan, R. Qi, D. R. Roe, A. Roitberg, C. Sagui, S. Schott-Verdugo, J. Shen, C. L. Simmerling, J. Smith, R. SalomonFerrer, J. Swails, R. C. Walker, J. Wang, H. Wei, R. M. Wolf, X. Wu, L. Xiao, D. M. York, P. A. Kollman, AMBER 18, University of California, San Francisco, 2018.

J.-P. Ryckaert, G. Ciccotti, H. J. C. Berendsen, J. Comput. Phys. 1977, 23, 327-341.

C. W. Hopkins, S. Le Grand, R. C. Walker, A. E. Roitberg, J. Chem. Theory Comput. 2015, 11, 1864-1874.

K. L. Howe, B. J. Bolt, M. Shafie, P. Kersey, M. Berriman, Mol. Biochem. Parasitol. 2017, 215, 2-10.

W. J. Kent, Genome Res. 2002, 12, 656-664.

Quadruplexes with a grain of salt: influence of cation type and concentration on DNA G4 stability