Arrangements of human telomere DNA quadruplex in physiologically relevant K ⁺ solutions

Abstract

The arrangement of the human telomeric quadruplex in physiologically relevant conditions has not yet been unambiguously determined. Our spectroscopic results suggest that the core quadruplex sequence G ₃(TTAG ₃) ₃ forms an antiparallel quadruplex of the same basket type in solution containing either K ⁺ or Na ⁺ ions. Analogous sequences extended by flanking nucleotides form a mixture of the antiparallel and hybrid (3 + 1) quadruplexes in K ⁺-containing solutions. We, however, show that long telomeric DNA behaves in the same way as the basic G ₃(TTAG ₃) ₃ motif. Both G ₃(TTAG ₃) ₃ and long telomeric DNA are also able to adopt the (3 + 1) quadruplex structure: Molecular crowding conditions, simulated here by ethanol, induced a slow transition of the K ⁺-stabilized quadruplex into the hybrid quadruplex structure and then into a parallel quadruplex arrangement at increased temperatures. Most importantly, we demonstrate that the same transitions can be induced even in aqueous, K ⁺-containing solution by increasing the DNA concentration. This is why distinct quadruplex structures were detected for AG ₃(TTAG ₃) ₃ by X-ray, nuclear magnetic resonance and circular dichrosim spectroscopy: Depending on DNA concentration, the human telomeric DNA can adopt the antiparallel quadruplex, the (3 + 1) structure, or the parallel quadruplex in physiologically relevant concentrations of K ⁺ ions.