Mismatch Repair of Cis-diamminedichloroplatinum(II)-induced DNA Damage

Because cytotoxicity by an alkylating agent such as N-methyl-N'-nitrosoguanidine is markedly increased in adenine methylase-deficient dam-3 Escherichia coli, it was of interest to assess whether mismatch repair was similarly important in the repair of DNA damage induced by cis-diamminedichloroplatinum(II) (CDDP). The results demonstrate that after exposure to 5-40 microM CDDP, dam-3 E. coli are 2-15-fold more sensitive to the cytotoxic effects of this agent. Further, dam-3 mutL451 E. coli deficient in mismatch repair was as resistant as wild type. trans-Diamminedichloroplatinum(II) treatment did not cause marked increments in cytotoxicity in dam-3 E. coli compared to wild type. The rate of excision of platinum was significantly reduced in dam-3 E. coli compared to wild type, demonstrating that differences in the repair of CDDP-induced DNA damage underlie enhanced cytotoxicity by this agent. Lastly, mutagenesis by CDDP was abrogated in umuDC- E. coli, showing that this gene product mediates mutagenesis by this agent.