SUPERCOILING AFFECTS THE ACCESSIBILITY OF GLUTATHIONE TO DNA-BOUND MOLECULES - POSITIVE SUPERCOILING INHIBITS CALICHEAMICIN-INDUCED DNA-DAMAGE

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 tha t the enediyne calicheamicin gamma(1)(I), a strand-breaking agent spec ific to the minor groove, causes approximate to 50% more damage in neg atively supercoiled plasmid DNA than in DNA with positive superhelicit y. Furthermore, we show that the decrease in damage in positively supe rcoiled DNA is controlled at the level of thiol activation of the drug . Our results suggest that supercoiling may affect both the activity o f nonintercalating genotoxins in vivo and the accessibility of glutath ione and other small physiologic molecules to DNA-bound chemicals or r eactions occurring in the grooves of DNA.