title: Different effects on human topoisomerase I by minor groove and intercalated deoxyguanosine adducts derived from two polycyclic aromatic hydrocarbon diol epoxides at or near a normal cleavage site.
abstract: Topoisomerase I (top1) relieves supercoiling in DNA by forming transient covalent cleavage complexes. These cleavage complexes can accumulate in the presence of damaged DNA or anticancer drugs that either intercalate or lie in the minor groove. Recently we reported that covalent diol epoxide (DE) adducts of benzo[a]pyrene (BaP) at the exocyclic amino group of G(+1) block cleavage at a preferred cleavage site ( approximately CTT-G(+1)G(+2)A approximately ) and cause accumulation of cleavage products at remote sites. In the present study, we have found that the 10S G(+2) adduct of BaP DE, which lies toward the scissile bond in the minor groove, blocks normal cleavage, whereas the 10R isomer, which orients away from this bond, allows normal cleavage but blocks religation. In contrast to BaP, the pair of benzo[c] phenanthrene (BcPh) DE adducts at G(+2), which intercalate from the minor groove either between G(+1)/G(+2) or between G(+2)/A, allow normal cleavage but block religation. Both intercalated BcPh DE adducts at G(+1) suppress normal cleavage, as do both groove bound BaP DE adducts at this position. These studies demonstrate that these DE adducts provide a novel set of tools to study DNA topoisomerases and emphasize the importance of contacts between the minor groove and top1's catalytic site.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA. pommier@nih.gov
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Glenda
authors.initials: G
authors.lastname: Kohlhagen
authors.forename: Gary S
authors.initials: GS
authors.lastname: Laco
authors.forename: Heiko
authors.initials: H
authors.lastname: Kroth
authors.forename: Jane M
authors.initials: JM
authors.lastname: Sayer
authors.forename: Donald M
authors.initials: DM
authors.lastname: Jerina
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D003849:Deoxyguanosine / Q000378:metabolism*; D004852:Epoxy Compounds / Q000494:pharmacology*; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D018736:DNA Adducts; D018076:DNA, Complementary; D004852:Epoxy Compounds; D007364:Intercalating Agents; D009841:Oligonucleotides; D011084:Polycyclic Aromatic Hydrocarbons; D011994:Recombinant Proteins; D004247:DNA; D010727:Phosphoric Diester Hydrolases; D004264:DNA Topoisomerases, Type I; D003849:Deoxyguanosine