DNA-DAMAGE AND MUTAGENESIS BY RADIOMIMETIC DNA-CLEAVING AGENTS - BLEOMYCIN, NEOCARZINOSTATIN AND OTHER ENEDIYNES

Bleomycin and the enediyne antibiotics effect concerted, simultaneous site-specific free radical attack on sugar moieties in both strands of DNA, resulting in double-strand breaks of defined geometry and chemic al structure, as well as abasic sites with closely opposed strand brea ks. The hypersensitivity of several mammalian double-strand break repa ir-deficient mutants to these agents confirms the role of these double -strand breaks in mediating cytotoxicity. In bacteria, mutagenesis by both bleomycin and neocarzinostatin appears to result from replicative bypass of abasic sites, the repair of which is blocked by the presenc e of closely opposed strand breaks. However, in mammalian cells, such abasic sites decompose to form double-strand breaks, and mutagenesis c onsists primarily of small deletions, large deletions, and gene rearra ngements, all of which probably result from errors in double-strand br eak repair by a nonhomologous end-joining mechanism. Studies with the radiomimetic antibiotics emphasize the importance of this end-joining repair pathway, and these agents provide useful probes of its mechanis tic details, particularly the effects of chemically modified DNA termi ni on repair.