The Effect of Reductant Levels on the Formation of Damage Lesions Derived from a 2-Deoxyribose Radical in ssDNA

Abstract

Thiols play a major role in the outcome of oxidative damage to DNA when it is initiated through cellular exposure to ionizing radiation. DNA radicals formed under aerobic conditions are converted to peroxyl radicals through trapping by oxygen at a diffusion-controlled rate. As a primary source of cellular reductant, thiols are responsible for the conversion of these DNA-derived peroxyl radicals to their corresponding hydrogen peroxides and subsequent strand breaks. Through the use of modified nucleotides, which act as precursors to nucleic acid radicals, we have investigated the effect of varying amounts of the cellular thiol glutathione (GSH) on the distribution of damage products produced from a 2-deoxyribose radical in DNA: the C3'-thymidinyl radical. The C3'-thymidinyl radical results from the abstraction of a hydrogen atom from the C3'-position of DNA oligomers at a thymidine residue, and is known to deliver several DNA damage lesions including the 3'-phosphoglycolaldehyde, 3'-phosphoglycolate and a 5'-aldehyde. Here we show that the level of GSH present has an impact on the level of production of these C3'-thymidinyl radical derived damage products.