Molecular mechanism of heavy rare earth elements-induced G-quadruplex DNA: Structural switch in human telomeric variants.

Abstract

Heavy rare earth elements (HREEs) are vital to modern technologies, yet their interactions with nucleic acids remain underexplored to date. With rising environmental exposure, their potential to modulate telomeric DNA structures raises concerns about genomic stability. In this study, we demonstrate that micromolar concentrations of HREEs induce stable G-quadruplexes (GQs) in human telomeric DNA and its variants. Conformational study revealed the formation of antiparallel GQs across all telomeric variants; thermal analysis further confirmed sequence-dependent differences in GQ stability, with thymine-rich loops exhibiting enhanced structural stability. To validate GQ formation, ¹H NMR spectroscopy was employed, providing direct evidence of Hoogsteen hydrogen bonding. Binding affinity and stoichiometry were determined through thermodynamic characterization, revealing a 2:1 HREE-DNA stoichiometry and favorable binding energetics. Vibrational spectroscopic analysis further revealed characteristic shifts associated with guanine ring and phosphate backbone interactions. The impact of metal coordination on structural charge distribution was evaluated through zeta potential analysis, which revealed significant electrostatic shifts upon GQ formation. Finally, Competitive binding studies demonstrated that HREEs displace Na⁺/K⁺ ions, resulting in conformational transitions. Collectively, these findings provide detailed insight into HREE-induced GQ formation, with implications for telomere biology, environmental toxicity, and nucleic acid-based biosensing.