Structural polymorphism of intramolecular quadruplex of human telomeric DNA: effect of cations, quadruplex-binding drugs and flanking sequences

• Published in: Nucleic acids research Vol. 36; no. 12; pp. 4079 - 4087
• Main Authors: Gaynutdinov, Timur I, Neumann, Ronald D, Panyutin, Igor G
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.07.2008; Oxford Publishing Limited (England)
• Subjects: antineoplastic activity; antineoplastic agents; Base Sequence; Cations; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - drug effects; DNA damage; Drugs; G-Quadruplexes - drug effects; Humans; Iodine Radioisotopes; ligands; nucleotides; Oligodeoxyribonucleotides - chemistry; Oxazoles - pharmacology; Porphyrins - pharmacology; Potassium - pharmacology; potassium chloride; Repetitive Sequences, Nucleic Acid; Sodium - pharmacology; Sodium chloride; Structural Biology; Telomere - chemistry; telomeres
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkn351

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 G₃(TTAG₃)₃ were the subject of multiple studies. Here, we employ ¹²⁵I-radioprobing, a method based on analysis of the distribution of DNA breaks after decay of ¹²⁵I 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[G₃(TTAG₃)₃¹²⁵I-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[G₃(TTAG₃)₃¹²⁵I-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[G₃(TTAG₃)₃¹²⁵I-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.