ENEDIYNE-MEDIATED DNA-DAMAGE IN NUCLEI IS MODULATED AT THE LEVEL OF THE NUCLEOSOME

DNA damage in HeLa nuclei and isolated nucleosome core particles has b een examined for several members of the enediyne family of antitumor a ntibiotics: calicheamicin gamma(1)(I) (CAL), esperamicin A(1) (ESP A1) , esperamicin C (ESP C), and neocarzinostatin (NCS). In nuclei, both N CS and ESP A1 produced DNA damage limited to the linker region of the nucleosome, while CAL and ESP C, an analog of ESP A1 missing the deoxy fucose-anthranilate moiety, damaged both the core and linker DNA. DNA fragments produced by CAL and ESP C in the nucleosome core occurred wi th a 10-11-nucleotide periodicity similar to that produced by DNase I, while damage produced by NCS and ESP A1 appeared to be limited to the terminal portions of the core DNA The damage in nuclei is shown to be caused directly by the drugs with little contribution from endogenous factors, such as nucleases and topoisomerases. Features of drug struc ture that may limit damage to the nucleosome core include the presence of substituents on both sides of the CAL/ESP-type core, and the prese nce of an intercalating moiety, such as the naphthoate of NCS and poss ibly the anthranilate of ESP A1.