title: Supercoiling affects the accessibility of glutathione to DNA-bound molecules: positive supercoiling inhibits calicheamicin-induced DNA damage.
abstract: DNA superhelical tension, an important feature of genomic organization, is known to affect the interactions of intercalating molecules with DNA. However, the effect of torsional tension on nonintercalative DNA-binding chemicals has received less attention. We demonstrate here that the enediyne calicheamicin gamma1I, a strand-breaking agent specific to the minor groove, causes approximately 50% more damage in negatively supercoiled plasmid DNA than in DNA with positive superhelicity. Furthermore, we show that the decrease in damage in positively supercoiled DNA is controlled at the level of thiol activation of the drug. Our results suggest that supercoiling may affect both the activity of nonintercalating genotoxins in vivo and the accessibility of glutathione and other small physiologic molecules to DNA-bound chemicals or reactions occurring in the grooves of DNA.
authors.affiliation: Division of Toxicology, 56-787, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: LaMarr
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: P C
authors.initials: PC
authors.lastname: Dedon
mesh_terms: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D019843:Archaeal Proteins; D004249:DNA Damage; D004278:DNA, Superhelical / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D053281:Enediynes; D004926:Escherichia coli; D005978:Glutathione / Q000378:metabolism*; D006657:Histones; D008956:Models, Chemical; D009153:Mutagens / Q000494:pharmacology*; D009690:Nucleic Acid Conformation; D013864:Thioglycolates / Q000494:pharmacology
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D019843:Archaeal Proteins; D004278:DNA, Superhelical; D004268:DNA-Binding Proteins; D053281:Enediynes; C065108:HMf protein, Archaeal; D006657:Histones; D009153:Mutagens; D013864:Thioglycolates; C055955:calicheamicin gamma(1)I; D005978:Glutathione; C037474:methyl thioglycolate