Double-Strand Breaks from a Radical Commonly Produced by DNA-Damaging Agents

[Image: see text] Double-strand breaks are widely accepted to be the most toxic form of DNA damage. Molecules that produce double-strand breaks via a single chemical event are typically very cytotoxic and far less common than those that form single-strand breaks. It was recently reported that a commonly formed C4′-radical produces double-strand breaks under aerobic conditions. Experiments described herein indicate that a peroxyl radical initiates strand damage on the complementary strand via C4′-hydrogen atom abstraction. Inferential evidence suggests that a C3′-peroxyl radical induces complementary strand damage more efficiently than does a C4′-peroxyl radical. Complementary strand hydrogen atom abstraction by the peroxyl radical is efficiently quenched by thiols. This mechanism could contribute to the higher than expected yield of double-strand breaks produced by ionizing radiation.