The Equally Important Role of Adenine Derivatives to That of Pyrimidine Derivatives in Near-0 eV Electron-Induced DNA Lesions.

Abstract

The role of adenine (A) derivatives in DNA damage is scarcely studied due to the low electron affinity of base A. Experimental studies demonstrate that low-energy electron (LEE) attachment to adenine derivatives complexed with amino acids induces barrier-free proton transfer producing the neutral N7 -hydrogenated adenine radicals rather than conventional anionic species. To explore possible DNA lesions at the A sites under physiological conditions, probable bond ruptures in two models-N7 -hydrogenated 2'-deoxyadenosine-3'-monophosphate (3'-dA(N7H)MPH) and 2'-deoxyadenosine-5'-monophosphate (5'-dA(N7H)MPH), without and with LEE attachment-are studied by DFT. In the neutral cases, DNA backbone breakage and base release resulting from C3' -O3' and N9 -C1' bond ruptures, respectively, by an intramolecular hydrogen-transfer mechanism are impossible due to the ultrahigh activation energies. On LEE attachment, the respective C3' -O3' and N9 -C1' bond ruptures in [3'-dA(N7H)MPH](-) and [5'-dA(N7H)MPH](-) anions via a pathway of intramolecular proton transfer (PT) from the C2' site of 2'-deoxyribose to the C8 atom of the base moiety become effective, and this indicates that substantial DNA backbone breaks and base release can occur at non-3'-end A sites and the 3'-end A site of a single-stranded DNA in the physiological environment, respectively. In particular, compared to the results of previous theoretical studies, not only are the electron affinities of 3'-dA(N7H)MPH and 5'-dA(N7H)MPH comparable to those of hydrogenated pyrimidine derivatives, but also the lowest energy requirements for the C3' -O3' and N9 -glycosidic bond ruptures in [3'-dA(N7H)MPH](-) and [5'-dA(N7H)MPH](-) anions, respectively, are comparable to those for the C3' -O3' and N1 -glycosidic bond cleavages in corresponding anionic hydrogenated pyrimidine derivatives. Thus, it can be concluded that the role of adenine derivatives in single-stranded DNA damage is equally important to that of pyrimidine derivatives in an irradiated cellular environment.