Nucleobase radicals are the major intermediates generated by the direct (e.g., dA(center dot+)) and indirect (e.g., dA center dot) effects of gamma-radiolysis. dA center dot was independently generated in DNA for the first time. The dA(center dot+)/dA. equilibrium, and consequently the reactivity in DNA, is significantly shifted toward the radical cation by a flanking dA. Tandem lesions emanating from dA center dot are the major products when the reactive intermediate is flanked by a 5'-dGT. In contrast, when dA center dot is flanked by dA, the increased dA(center dot+) 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.