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 been examined for several members of the enediyne family of antitumor antibiotics: calicheamicin gamma 1I (CAL), esperamicin A1 (ESP A1), esperamicin C (ESP C), and neocarzinostatin (NCS). In nuclei, both NCS 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 deoxyfucose-anthranilate moiety, damaged both the core and linker DNA. DNA fragments produced by CAL and ESP C in the nucleosome core occurred with 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 structure that may limit damage to the nucleosome core include the presence of substituents on both sides of the CAL/ESP-type core, and the presence of an intercalating moiety, such as the naphthoate of NCS and possibly the anthranilate of ESP A1.
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Division of Toxicology, Massachusetts Institute of Technology, Cambridge 02139.
Goldberg
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Dedon
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D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000633:toxicity*; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004492:Edetic Acid / Q000494:pharmacology; D053281:Enediynes; D005978:Glutathione / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D009707:Nucleosomes / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D009707:Nucleosomes; C061506:esperamicin C; D004492:Edetic Acid; D005978:Glutathione; C047543:esperamicin A1