Radiation vs Chemical Damage to DNA

Ionizing radiation is considered to cause its damage to cellular DNA via OH free ¡radicals and by direct ionization of the DNA (1). In attempting to simulate the OH portion of this damage we have used hydrogen peroxide (2). We showed that the probable mechanism of damage production by this agent was through OH radicals produced by its interaction with variable valency metal ions bound to DNA (in a Fenton type reaction). Previously it had been shown that hydrogen peroxide treatment causes single-strand breaks (SSB) (but not double-strand breaks, DSB) in cellular DNA (3). More recently the reaction of hydrogen peroxide with DNA was found to give the same range of base-damaged products as that formed by low-LET ionizing radiation (4). Therefore, the spectrum of all damage types and their relative yields produced in the individual moieties of the DNA (sugar and base) by OH radicals is the same for hydrogen peroxide as for low-LET ionizing radiation (5). When cells are treated with hydrogen peroxide at 0°C, killing does not occur until the number of SSB present (and the base damage concomitantly produced) is 2,600 times higher than that present when equivalent cell kill is induced by ionizing radiation (2). Clearly although the same damage types are formed by hydrogen peroxide their presence is inconsequential to the cell survival. We conclude that it is not the chemical structure of the OH radical-damaged sites per se which is responsible for the ionizing radiation-induced cell killing. It is the concentration of these damaged sites in local regions of the DNA (producing what we have called locally multiply damaged sites, LMDS) which is responsible for the effectiveness of ionizing radiation in inducing cell killing.