Streptonigrin-induced topoisomerase II sites exhibit base preferences in the middle of the enzyme stagger.
The non DNA intercalator streptonigrin was shown to inhibit topoisomerase II by stabilizing cleavable complexes (Yamashita et al, Cancer Res. 1990, 50, 5841). Streptonigrin-induced topoisomerase II cleavage sites were mapped in the c-myc proto-oncogene DNA. Streptonigrin induced a unique cleavage pattern. Its cleavage sites were less frequent than those induced by other topoisomerase II inhibitors. Strongly preferred bases were found in the middle of topoisomerase II DNA stagger, with thymine at position +2 and adenine at position +3, position +1 being the nucleotide covalently linked to topoisomerase II. Preference for bases not immediately flanking the cleavage sites has not been reported previously and indicates that a mechanism other than "drug stacking" within the DNA break is taking place with streptonigrin to stabilize cleavable complexes. An alternative model taking into account the unusual DNA binding properties of streptonigrin is proposed.
Leteurtre
F
F
Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, MD 20892.
Kohlhagen
G
G
Pommier
Y
Y
D001483:Base Sequence; D001665:Binding Sites; D003300:Copper / Q000494:pharmacology; D003596:Cytosine / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D005091:Exons; D016259:Genes, myc; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D013308:Streptonigrin / Q000378:metabolism / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D059005:Topoisomerase II Inhibitors; D013308:Streptonigrin; D003300:Copper; D003596:Cytosine; D004247:DNA; D004250:DNA Topoisomerases, Type II