Structural polymorphism of intramolecular quadruplex of human telomeric DNA: effect of cations, quadruplex-binding drugs and flanking sequences.
G-quadruplex structures formed in the telomeric DNA are thought to play a role in the telomere function. Drugs that stabilize the G-quadruplexes were shown to have anticancer effects. The structures formed by the basic telomeric quadruplex-forming unit G(3)(TTAG(3))(3) were the subject of multiple studies. Here, we employ (125)I-radioprobing, a method based on analysis of the distribution of DNA breaks after decay of (125)I incorporated into one of the nucleotides, to determine the fold of the telomeric DNA in the presence of TMPyP4 and telomestatin, G-quadruplex-binding ligands and putative anticancer drugs. We show that d[G(3)(TTAG(3))(3)(125)I-CT] adopts basket conformation in the presence of NaCl and that addition of either of the drugs does not change this conformation of the quadruplex. In KCl, the d[G(3)(TTAG(3))(3)(125)I-CT] is most likely present as a mixture of two or more conformations, but addition of the drugs stabilize the basket conformation. We also show that d[G(3)(TTAG(3))(3)(125)I-CT] with a 5'-flanking sequence folds into (3+1) type 2 conformation in KCl, while in NaCl it adopts a novel (3+1) basket conformation with a diagonal central loop. The results demonstrate the structural flexibility of the human telomeric DNA; and show how cations, quadruplex-binding drugs and flanking sequences can affect the conformation of the telomeric quadruplex.
Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892-1180, USA.
Timur I
TI
Gaynutdinov
Ronald D
RD
Neumann
Igor G
IG
Panyutin
D001483:Base Sequence; D002412:Cations; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects; D006801:Humans; D007457:Iodine Radioisotopes; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010080:Oxazoles / Q000494:pharmacology; D011166:Porphyrins / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D012091:Repetitive Sequences, Nucleic Acid; D012964:Sodium / Q000494:pharmacology; D016615:Telomere / Q000737:chemistry*
D002412:Cations; D007457:Iodine Radioisotopes; D009838:Oligodeoxyribonucleotides; D010080:Oxazoles; D011166:Porphyrins; C431888:telomestatin; C021096:tetra(4-N-methylpyridyl)porphine; D004247:DNA; D012964:Sodium; D011188:Potassium