Delineation of the Chemical Pathways Underlying Nitric Oxide-Induced Homologous Recombination in Mammalian Cells Original Research Article

Inflammation is an important risk factor for cancer. During inflammation, macrophages secrete nitric oxide (NO•), which reacts with superoxide or oxygen to create ONOO− or N2O3, respectively. Although homologous recombination causes DNA sequence rearrangements that promote cancer, little was known about the ability of ONOO− and N2O3 to induce recombination in mammalian cells. Here, we show that ONOO− is a potent inducer of homologous recombination at an integrated direct repeat substrate, whereas N2O3 is relatively weakly recombinogenic. Furthermore, on a per lesion basis, ONOO−-induced oxidative base lesions and single-strand breaks are significantly more recombinogenic than N2O3-induced base deamination products, which did not induce detectable recombination between plasmids. Similar results were observed in mammalian cells from two different species. These results suggest that ONOO−-induced recombination may be an important mechanism underlying inflammation-induced cancer.