Purified diets lacking nucleic acids and/or methyl donors (folate, choline, methionine) result in increased ratios of soluble uridine/thymidine deoxyribonucleotide triphosphates (dUTP/dTTP) and delay progression of hepatocytes through S-phase of the cell cycle during liver regeneration. To determine if this is due to DNA damage, rats were fed either a purified basal methyl-deficient diet (lacking folate, methonine, and choline) or basal diet supplemented with: 1) folic acid, methionine, and choline; 2) methionine and choline; 3) yeast RNA; 4) calf thymus DNA; or 5) methionine, choline, and yeast RNA. Levels of dUTP and dTTP (HPLC analysis) and relative amounts of DNA strand breaks (ROPS asssay) were determined. There was a two-fold increase in both dUTP/dTTP ratios and DNA strand breaks in the basal diet compared to basal diet supplemented with methyl donors. Addition of RNA or DNA to the basal diet reduced both dUTP/dTTP ratios and DNA strand breaks. Linear regression analysis of the results indicated a direct correlation of dUTP/dTTP ratios with the level of DNA strand breaks (R= 0.94; p<0.006). This may partially explain the increased carcinogenicity of diets deficient in nucleic acids and/or methyl donors.