Multiple pathways of recombination define cellular responses to cisplatin

Background: Cisplatin is a DNA-damaging drug used for treatment of testicul ar tumors. The toxicity of cisplatin probably results from its ability to f orm DNA adducts that inhibit polymerases. Blocked replication represents a particular challenge for tumor cells, which are committed to unremitting di vision. Recombination provides a mechanism by which replication can proceed despite the presence of lesions and therefore could be significant for man aging cisplatin toxicity. Results: Recombination-deficient Escherichia coli mutants were strikingly s ensitive to cisplatin when compared with the parental strain. Our data iden tified both daughter-strand gap and double-strand break recombination pathw ays as critical for survival following treatment with cisplatin. Although i t is established that nucleotide excision repair (NER) significantly protec ts against cisplatin toxicity, most recombination-deficient strains were as sensitive to the drug as the NER-deficient uvrA mutant. Recombination/NER deficient double mutants were more sensitive to cisplatin than the correspo nding single mutants, suggesting that recombination and NER pathways play i ndependent roles in countering cisplatin toxicity. Cisplatin was a potent r ecombinogen in comparison with the trans isomer and canonical alkylating ag ents. Mitomycin C, which like cisplatin, forms DNA cross-links, was also re combinogenic at minimally toxic doses. Conclusions: We have demonstrated that all of the major recombination pathw ays are critical for E. coli survival following treatment with cisplatin. M oreover, recombination pathways act independently of NER and are of equal i mportance to NER as genoprotective systems against cisplatin toxicity. Take n together, these results shed new light on how cells survive and succumb t o this widely used anticancer drug.