Delineation of the chemical pathways underlying nitric oxide-induced homologous recombination in mammalian cells.
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.
Kiziltepe
Tanyel
T
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Yan
Amy
A
Dong
Min
M
Jonnalagadda
Vidya S
VS
Dedon
Peter C
PC
Engelward
Bevin P
BP
D000818:Animals; D019556:COS Cells; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002522:Chlorocebus aethiops; D004247:DNA / Q000235:genetics; D051379:Mice; D009569:Nitric Oxide / Q000494:pharmacology* / Q000502:physiology; D010957:Plasmids; D011995:Recombination, Genetic / Q000187:drug effects* / Q000502:physiology; D012091:Repetitive Sequences, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D009569:Nitric Oxide; D004247:DNA