Calicheamicin-Mediated DNA Damage in a Reconstituted Nucleosome Is Not Affected by Histone Acetylation: The Role of Drug Structure in the Target Recognition Process

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Abstract
We have examined the role of drug structure and histone acetylation in DNA damage produced by the enediyne antibiotic calicheamicin γ1I in nucleosomes reconstituted onto the 5S rRNA gene of Xenopus borealis. Consistent with previous observations, calicheamicin damage at the 3‘-end of a purine tract (positions −13 and −14) was enhanced in the nucleosome compared to naked DNA while damage at other sites was somewhat reduced in the nucleosome. However, damage produced by esperamicin C, an analog of calicheamicin missing the terminal sugar-aromatic ring in the side chain, showed no enhancement at positions −13 and −14, and its sequence selectivity in naked DNA was markedly different from that of calicheamicin. This highlights the importance of the intact tetrasaccharide side chain in the recognition of the structural deformation occurring at the 3‘-ends of purine tracts. Both drugs produced identical cleavage patterns in normal and hyperacetylated nucleosomes. Given the sensitivity of calicheamicin to local DNA conformation, this observation is consistent with other studies that suggest that histone acetylation alone does not significantly affect the local conformation of core DNA in the nucleosome.