What Is the Initial Chemical Precursor of DNA Strand Breaks Generated by Direct-Type Effects?

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What Is the Initial Chemical Precursor of DNA Strand Breaks Generated by Direct-Type Effects?

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The present study tests the hypothesis that the majority of DNA strand breaks produced by direct-type effects are due to sugar free radical precursors and that these radicals are produced by direct ionization of the sugar–phosphate backbone or by hole transfer to the sugar from tightly bound water. Well-defined crystalline DNA samples of d(CGCG)2, d(CGCACG:GCGTGC), d(GTGCGCAC)2, and d((GCACGCGTGC)2 were irradiated at 4 K, and their free radical dose response determined from 0 to 1800 kGy. A model is proposed that effectively describes the dose response curves. It includes the following parameters: the free radical concentration at saturation Cmax, the free radical yields Gb and Gs, and the destruction constants kb and ks. The subscripts b and s refer to base-centered and sugar-centered radicals, respectively. In each of these systems, the free radical concentration exhibits a remarkable resistance to dose saturation up to at least 1500 kGy. As predicted, Gb > Gs, the Gb/Gs ratio varying between 4 and 12. Likewise, kb > ks, the kb/ks ratio varying between 28 and 81. The lower cross-section for destruction of the sugar-centered radicals is consistent with the expectation that they are relatively radiation resistant. Gb/G is between 0.81 and 0.92, indicating that at low doses the bases trap out 80–90% of the total free radical population. The remaining 10–20% are located on the sugar. At high dose, a larger fraction of the radicals are trapped on the backbone as seen from the ratio CmxS/CmxB, which ranges from 3.5 to 8. This unusually late onset of dose saturation closely parallels that observed for strand break products in earlier studies. There is, therefore, a good correlation between the dose response profiles of sugar-trapped radicals and strand breaks. These observations strongly support the hypothesis that sugar radicals are precursors to the majority of strand breaks produced by the direct-type effect in DNA.


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