EXCISION-REPAIR REDUCES DOXORUBICIN-INDUCED GENOTOXICITY

LacI mutations induced by doxorubicin in a wild-type, uvr(A)BC repair- proficient E. coli strain were analyzed by DNA sequencing. These mutat ions were contrasted with mutations previously recovered from doxorubi cin-treated uvrB- organisms in order to assess the role of excision re pair in doxorubicin-induced genotoxicity. After a 30-min exposure of w ild-type E. coli to 330 muM doxorubicin, survival was 34% and the over all lacI mutation frequency increased 1.8-fold to 340 X 10(-8). The di stribution of doxorubicin-induced mutants among subclasses of mutation involving the i(-d) and lac operator regions differed significantly b etween repair-proficient and -deficient strains. Distributional differ ences appeared to result both from a decrease in deletions involving t he lac operator and an increase in base substitutions involving the i( -d) region in repair proficient organisms. However, elements of the do xorubicin-induced mutation spectrum in uvrB- E. coli are still discern able in wild-type organisms. These elements include the remarkable shi ft of 3'-deletion endpoints to palindromic sequence within the lac ope rator and the recovery of multiple isolates of T:A --> A:T transversio ns at position 96 in doxorubicin-treated cultures. These observations suggest that components of the uvr(A)BC nucleotide excision repair sys tem function through a general mechanism prior to fixation of mutation s to reduce, but not completely eliminate, the genotoxic effects of do xorubicin.