Neocarzinostatin-induced DNA base release accompanied by staggered oxidative cleavage of the complementary strand.
Treatment of an end-labeled DNA restriction fragment with the nonprotein chromophore of neocarzinostatin induced lesions which, after treatment with endonuclease IV or putrescine, were expressed as site-specific double-strand breaks. Analysis of the termini at cleavage sites in each strand showed that the neocarzinostatin-induced lesions consisted of an apurinic/apyrimidinic site plus a closely opposed break in the complementary strand. The break always occurred opposite the base two positions upstream from the apurinic/apyrimidinic site and had the 3'-phosphate and 5'-aldehyde termini characteristic of neocarzinostatin-induced breaks. This positioning suggests that neocarzinostatin simultaneously attacks two DNA sugars on opposite edges of the minor groove. The sequence specificity for formation of apurinic/apyrimidinic sites with closely opposed breaks reflected that of neocarzinostatin-induced mutagenesis. The potent mutagenicity of these lesions may be attributable to the presence of closely opposed damage in both DNA strands.
Povirk
L F
LF
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Houlgrave
C W
CW
Han
Y H
YH
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D010582:Bacteriophage lambda / Q000235:genetics; D001483:Base Sequence; D004249:DNA Damage; D004279:DNA, Viral / Q000187:drug effects* / Q000235:genetics; D005814:Genes, Viral; D009154:Mutation; D009353:Zinostatin / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D004279:DNA, Viral; D009353:Zinostatin