DNA Damage Emanating From a Neutral Purine Radical Reveals the Sequence Dependent Convergence of the Direct and Indirect Effects of γ‑Radiolysis

Nucleobase radicals are the major intermediates generated by the direct (e.g., dA^•+) and indirect (e.g., dA•) effects of γ-radiolysis. dA• was independently generated in DNA for the first time. The dA^•+/dA• equilibrium, and consequently the reactivity in DNA, is significantly shifted toward the radical cation by a flanking dA. Tandem lesions emanating from dA• are the major products when the reactive intermediate is flanked by a 5′-dGT. In contrast, when dA• is flanked by dA, the increased dA^•+ pK_a results in DNA damage arising from hole transfer. This is the first demonstration that sequence effects lead to the intersection of the direct and indirect effects of ionizing radiation.