Absorption of Low-Energy UV Radiation by Human Telomere G‑Quadruplexes Generates Long-Lived Guanine Radical Cations

Telomeres, which are involved in cell division, carcinogenesis, and aging and constitute important therapeutic targets, are prone to oxidative damage. This propensity has been correlated with the presence of guanine-rich sequences, capable of forming four-stranded DNA structures (G-quadruplexes). Here, we present the first study on oxidative damage of human telomere G-quadruplexes without mediation of external molecules. Our investigation has been performed for G-quadruplexes formed by folding of GGG­(TTAGGG)<sub>3</sub> single strands in buffered solutions containing Na<sup>+</sup> cations (TEL21/Na<sup>+</sup>). Associating nanosecond time-resolved spectroscopy and quantum mechanical calculations (TD-DFT), it focuses on the primary species, ejected electrons and guanine radicals, generated upon absorption of UV radiation directly by TEL21/Na<sup>+</sup>. We show that, at 266 nm, corresponding to an energy significantly lower than the guanine ionization potential, the one-photon ionization quantum yield is 4.5 × 10<sup>–3</sup>. This value is comparable to that of cyclobutane thymine dimers (the major UV-induced lesions) in genomic DNA; the quantum yield of these dimers in TEL21/Na<sup>+</sup> is found to be (1.1 ± 0.1) × 10<sup>–3</sup>. The fate of guanine radicals, generated in equivalent concentration with that of ejected electrons, is followed over 5 orders of magnitude of time. Such a quantitative approach reveals that an important part of radical cation population survives up to a few milliseconds, whereas radical cations produced by chemical oxidants in various DNA systems are known to deprotonate, at most, within a few microseconds. Under the same experimental conditions, neither one-photon ionization nor long-lived radical cations are detected for the telomere repeat TTAGGG in single-stranded configuration, showing that secondary structure plays a key role in these processes. Finally, two types of deprotonated radicals are identified: on the one hand, (G-H<sub>2</sub>)<sup>•</sup> radicals, stable at early times, and on the other hand, (G-H<sub>1</sub>)<sup>•</sup> radicals, appearing within a few milliseconds and decaying with a time constant of ∼50 ms.