Abasic (AP) lesions are the most frequent type of damages occurring in cellular DNA. Here we describe the conformational effects of AP sites substituted for 2'-deoxyadenosine in the first (ap7), second (ap13) or third (ap19) loop of the quadruplex formed in K(+) by the human telomere DNA 5'-d[AG3(TTAG3)3]. CD spectra and electrophoresis reveal that the presence of AP sites does not hinder the formation of intramolecular quadruplexes. NMR spectra show that the structural heterogeneity is substantially reduced in ap7 and ap19 as compared to that in the wild-type. These two (ap7 and ap19) sequences are shown to adopt the hybrid-1 and hybrid-2 quadruplex topology, respectively, with AP site located in a propeller-like loop. All three studied sequences transform easily into parallel quadruplex in dehydrating ethanol solution. Thus, the AP site in any loop region facilitates the formation of the propeller loop. Substitution of all adenines by AP sites stabilizes the parallel quadruplex even in the absence of ethanol. Whereas guanines are the major determinants of quadruplex stability, the presence or absence of loop adenines substantially influences quadruplex folding. The naturally occurring adenine-lacking sites in the human telomere DNA can change the quadruplex topology in vivo with potentially vital biological consequences.

CEITEC Central European Institute of Technology Masaryk University Kamenice 5 CZ 625 00 Brno Czech Republic Institute of Biophysics Academy of Sciences of the Czech Republic v v i Královopolská 135 CZ 612 65 Brno Czech Republic

CEITEC Central European Institute of Technology Masaryk University Kamenice 5 CZ 625 00 Brno Czech Republic National Centre for Biomolecular Research Faculty of Science Masaryk University Kamenice 5 CZ 625 00 Brno Czech Republic

Rimstone Laboratory RLI 29 Lancaster Way Cheshire CT 06410 USA

Zobrazit více v PubMed

Wang Z. DNA damage and mutagenesis. In: Smart RC, Hodgson E, editors. Molecular and Biochemical Toxicology. John Wiley & Sons, Inc; 2007. pp. 441–491.

Nakamura J., Swenberg J.A. Endogenous apurinic/apyrimidinic sites in genomic DNA of mammalian tissues. Cancer Res. 1999;59:2522–2526. PubMed

Mellon I. DNA repair. In: Smart RC, Hodgson E, editors. Molecular and Biochemical Toxicology. John Wiley & Sons, Inc; 2007. pp. 493–535.

Gelfand C.A., Plum G.E., Grollman A.P., Johnson F., Breslauer K.J. Thermodynamic consequences of an abasic lesion in duplex DNA are strongly dependent on base sequence. Biochemistry. 1998;37:7321–7327. PubMed

Goljer I., Withka J.M., Kao J.Y., Bolton P.H. Effects of the presence of an aldehydic abasic site on the thermal stability and rates of helix opening and closing of duplex DNA. Biochemistry. 1992;31:11614–11619. PubMed

Sagi J., Hang B., Singer B. Sequence-dependent repair of synthetic AP sites in 15-mer and 35-mer oligonucleotides: role of thermodynamic stability imposed by neighbor bases. Chem. Res. Toxicol. 1999;12:917–923. PubMed

Sagi J., Guliaev A.B., Singer B. 15-mer DNA duplexes containing an abasic site are thermodynamically more stable with adjacent purines than with pyrimidines. Biochemistry. 2001;40:3859–3868. PubMed

Goljer I., Kumar S., Bolton P.H. Refined solution structure of a DNA heteroduplex containing an aldehydic abasic site. J. Biol. Chem. 1995;270:22980–22987. PubMed

Beger R.D., Bolton P.H. Structures of apurinic and apyrimidinic sites in duplex DNAs. J. Biol. Chem. 1998;273:15565–15573. PubMed

Goodman M., Cai H., Bloom L., Eritja R. Nucleotide insertion and primer extension at abasic template sites in different sequence contexts. In: Wallace SS, VanHouten B, Kow YW, editors. DNA Damage: Effects on DNA Structure and Protein Recognition. Vol. 726. New York: New York Academy of Sciences; 1994. pp. 132–143. PubMed

Kiyonari S., Tahara S., Shirai T., Iwai S., Ishino S., Ishino Y. Biochemical properties and base excision repair complex formation of apurinic/apyrimidinic endonuclease from Pyrococcus furiosus. Nucleic Acids Res. 2009;37:6439–6453. PubMed PMC

Völker J., Plum G.E., Klump H.H., Breslauer K.J. DNA repair and DNA triplet repeat expansion: the impact of abasic lesions on triplet repeat DNA energetics. J. Am. Chem. Soc. 2009;131:9354–9360. PubMed PMC

Völker J., Plum G.E., Klump H.H., Breslauer K.J. Energy crosstalk between DNA lesions: implications for allosteric coupling of DNA repair and triplet repeat expansion pathways. J. Am. Chem. Soc. 2010;132:4095–4097. PubMed PMC

Sagi J. G-quadruplexes incorporating modified constituents: a review. J. Biomol. Struct. Dyn. 2014;32:477–511. PubMed

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

Maizels N. Dynamic roles for G4 DNA in the biology of eukaryotic cells. Nat. Struct. Mol. Biol. 2006;13:1055–1059. PubMed

Zahler A.M., Williamson J.R., Cech T.R., Prescott D.M. Inhibition of telomerase by G-quartet DNA structures. Nature. 1991;350:718–720. PubMed

Maizels N. Quadruplexes and the Biology of G-Rich Genomic Regions. In: Neidle S, Balasubramanian S, editors. Quadruplex Nucleic Acids. Cambridge: RSC Publishing; 2007. pp. 228–252.

Esposito V., Martino L., Citarella G., Virgilio A., Mayol L., Giancola C., Galeone A. Effects of abasic sites on structural, thermodynamic and kinetic properties of quadruplex structures. Nucleic Acids Res. 2010;38:2069–2080. PubMed PMC

Skolakova P., Bednarova K., Vorlickova M., Sagi J. Quadruplexes of human telomere dG(3)(TTAG(3))(3) sequences containing guanine abasic sites. Biochem. Biophys. Res. Commun. 2010;399:203–208. PubMed

Fujimoto T., Nakano S., Miyoshi D., Sugimoto N. The effects of molecular crowding on the structure and stability of G-quadruplexes with an abasic site. J. Nucleic Acids. 2011;2011:1–9. PubMed PMC

Virgilio A., Petraccone L., Esposito V., Citarella G., Giancola C., Galeone A. The abasic site lesions in the human telomeric sequence d[TA(G3T2A)3G3]: a thermodynamic point of view. BBA - Gen. Subjects. 2012;1820:2037–2043. PubMed

Esposito V., Oliviero G., Pepe A., Virgilio A., Galeone A. Studies on the influence of inversion of polarity sites on the dG residues glycosidic conformation in quadruplex structures. Nucleic Acids Symp. Ser. 2008;52:177–178. PubMed

Rachwal P.A., Brown T., Fox K.R. Sequence effects of single base loops in intramolecular quadruplex DNA. FEBS Lett. 2007;581:1657–1660. PubMed

Beckett J., Burns J., Broxson C., Tornaletti S. Spontaneous DNA lesions modulate DNA structural transitions occurring at nuclease hypersensitive element III1 of the human c-myc proto-oncogene. Biochemistry. 2012;51:5257–5268. PubMed

Dai J., Carver M., Yang D. Polymorphism of human telomeric quadruplex structures. Biochimie. 2008;90:1172–1183. PubMed PMC

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

Parkinson G.N., Lee M.P.H., Neidle S. Crystal structure of parallel quadruplexes from human telomeric DNA. Nature. 2002;417:876–880. PubMed

Ambrus A., Chen D., Dai J., Bialis T., Jones R.A., Yang D. Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution. Nucleic Acids Res. 2006;34:2723–2735. PubMed PMC

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. J. Am. Chem. Soc. 2006;128:9963–9970. PubMed PMC

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 Res. 2007;35:2440–2450. PubMed PMC

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 Res. 2007;35:4927–4940. PubMed PMC

Phan A.T., Kuryavyi V., Luu K.N., Patel D.J. Structure of two intramolecular G-quadruplexes formed by natural human telomere sequences in K+ solution. Nucleic Acids Res. 2007;35:6517–6525. PubMed PMC

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. J. Am. Chem. Soc. 2009;131:4301–4309. PubMed PMC

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 Res. 2010;38:1009–1021. PubMed PMC

Lim K.W., Ng V.C.M., Martín-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 Res. 2013;41:10556–10562. PubMed PMC

Dias E., Battiste J.L., Williamson J.R. Chemical probe for glycosidic conformation in telomeric DNAs. J. Am. Chem. Soc. 1994;116:4479–4480.

Xu Y., Noguchi Y., Sugiyama H. The new models of the human telomere d[AGGG(TTAGGG)3] in K+ solution. Bioorg. Med. Chem. 2006;14:5584–5591. PubMed

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. Chem. Commun. 2012;48:11425–11427. PubMed

Risitano A., Fox K.R. Influence of loop size on the stability of intramolecular DNA quadruplexes. Nucleic Acids Res. 2004;32:2598–2606. PubMed PMC

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

Rachwal P.A., Findlow I.S., Werner J.M., Brown T., Fox K.R. Intramolecular DNA quadruplexes with different arrangements of short and long loops. Nucleic Acids Res. 2007;35:4214–4222. PubMed PMC

Vorlickova M., Bednarova K., Kejnovska I., Kypr J. Intramolecular and intermolecular guanine quadruplexes of DNA in aqueous salt and ethanol solutions. Biopolymers. 2007;86:1–10. PubMed

Bugaut A., Balasubramanian S. A sequence-independent study of the influence of short loop lengths on the stability and topology of intramolecular DNA G-quadruplexes. Biochemistry. 2008;47:689–697. PubMed PMC

Guédin A., De Cian A., Gros J., Lacroix L., Mergny J.-L. Sequence effects in single-base loops for quadruplexes. Biochimie. 2008;90:686–696. PubMed

Guédin 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. PubMed PMC

Tippana R., Xiao W., Myong S. G-quadruplex conformation and dynamics are determined by loop length and sequence. Nucleic Acids Res. 2014;42:8106–8114. PubMed PMC

Palacky J., Vorlickova M., Kejnovska I., Mojzes P. Polymorphism of human telomeric quadruplex structure controlled by DNA concentration: a Raman study. Nucleic Acids Res. 2013;41:1005–1016. PubMed PMC

Gray D., Hung S., Johnson K. Absorption and circular-dichroism spectroscopy of nucleic-acid duplexes and triplexes. Methods Enzymol. 1995;246:19–34. PubMed

Phan A.T. Long-range imino proton-13C J-couplings and the through-bond correlation of imino and non-exchangeable protons in unlabeled DNA. J. Biomol. NMR. 2000;16:175–178. PubMed

Fiala R., Munzarová M.L., Sklenář V. Experiments for correlating quaternary carbons in RNA bases. J. Biomol. NMR. 2004;29:477–490. PubMed

Piotto M., Saudek V., Sklenar V. Gradient-tailored excitation for single-quantum NMR-spectroscopy of aqueous-solutions. J. Biomol. NMR. 1992;6:661–665. PubMed

Goddard T.D., Kneller D.G. SPARKY 3. San Francisco: University of California;

Vorlickova M., Kejnovska I., Sagi J., Renciuk D., Bednarova K., Motlova J., Kypr J. Circular dichroism and guanine quadruplexes. Methods. 2012;57:64–75. PubMed

Renciuk D., Kejnovska I., Skolakova P., Bednarova K., Motlova J., Vorlickova M. Arrangements of human telomere DNA quadruplex in physiologically relevant K+ solutions. Nucleic Acids Res. 2009;37:6625–6634. PubMed PMC

Vorlickova M., Tomasko M., Sagi A.J., Bednarova K., Sagi J. 8-Oxoguanine in a quadruplex of the human telomere DNA sequence. FEBS J. 2012;279:29–39. PubMed

Tomasko M., Vorlickova M., Sagi J. Substitution of adenine for guanine in the quadruplex-forming human telomere DNA sequence G(3)(T(2)AG(3))(3) Biochimie. 2009;91:171–179. PubMed

Sagi J., Renciuk D., Tomasko M., Vorlickova M. Quadruplexes of human telomere DNA analogs designed to contain G:A:G:A, G:G:A:A, and A:A:A:A tetrads. Biopolymers. 2010;93:880–886. PubMed

Kejnovska I., Vorlickova M., Brazdova M., Sagi J. Stability of human telomere quadruplexes at high DNA concentrations. Biopolymers. 2014;101:428–438. PubMed

Phan A.T., Patel D.J. A site-specific low-enrichment 15N, 13C isotope-labeling approach to unambiguous NMR spectral assignments in nucleic acids. J. Am. Chem. Soc. 2002;124:1160–1161. PubMed

Feigon J., Koshlap K.M., Smith F.W. H-1 NMR spectroscopy of DNA triplexes and quadruplexes. Methods Enzymol. 1995;261:225–255. PubMed

Loop permutation affects the topology and stability of G-quadruplexes

i-Motif of cytosine-rich human telomere DNA fragments containing natural base lesions

Clustered abasic lesions profoundly change the structure and stability of human telomeric G-quadruplexes