Homologous recombination is involved in the repair response of mammalian cells to low doses of tritium

Radioactive compounds incorporated in tissues can have biological effects resulting from energy deposition in subcellular compartments. We addressed the genetic consequences of [H-3] or [C-14]thymidine incorporation into mammalian DNA. Low doses of [H-3]thymidine in CHO cells led to enhanced sensitivity compared With [C-14]thymidine. Compared with wild-type cells, homologous recombination (HR)-deficient cells were more sensitive to lower doses of [H-3]thymidine but not to any dose of [C-14]thymidine. XRCC4-defective cells, however, were sensitive to both low and high doses of [H-3] and [C-14]thymidine, suggesting introduction of DNA double-strand breaks, which were confirmed by gamma-H2AX focus formation. While gamma rays induced measurable HR only at toxic doses, sublethal levels of [H-3] or [C-14]thymidine strongly induced HR. The level of stimulation was in an inverse relationship to the emitted energies. The RAD51 gene conversion pathway was involved, because [H-3]thymidine induced RAD51 foci, and [3(H)]thymidine-induced HR was abrogated by expression of dominant negative RAD51. In conclusion, both HR and non-homologous end-joining pathways were involved after labeled nucleotide incorporation (low doses); genetic effects were negatively correlated with the energy emitted but were positively correlated with the energy deposited in the nucleus, suggesting that low-energy R-particle emitters, at non-toxic doses, may induce genomic instability. (C) 2008 by Radiation Research Society.