An intercalation inhibitor altering the target selectivity of DNA damaging agents: Synthesis of site-specific aflatoxin B1 adducts in a p53 mutational hotspot

William R. Kobertz, David Wang, Gerald N. Wogan, John M. Essigmann

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Aflatoxin B1 (AFB1) is a potent human carinogen implicated in the etiology of hepatocellular carcinoma. Upon metabolic activation to the reactive epoxide, AFB1 forms DNA adducts primarily at the N7 position of guanines. To elucidate more fully the molecular mechanism of AFB1induced mutagenesis, an intercalation inhibitor was designed to probe the effects of intercalation by AFB1 epoxide on its reaction with DNA. DNA duplexes were prepared consisting of a target strand containing multiple potentially reactive guanines and a nontarget strand containing a cissyn thymidine- benzofuran photoproduct. Because the covalently linked benzofuran moiety physically occupies an intercalation site, we reasoned that such a site would be rendered inaccessible to AFB1 epoxide. By strategic positioning of this intercalation inhibitor in the intercalation site 5' to a specific guanine, the adduct yield at that site was greatly diminished, indicating that intercalation by AFB1 epoxide contributes favorably to adduct formation. Using this approach it has been possible to simplify the production of site- specifically modified oligonucleotides containing AFB1 adducts in the sequence context of n p53 mutational hotspot. Moreover, we report herein isolation of site-specifically AFB1-modified oligonucleotides in sequences containing multiple guanines. Use of intercalation inhibitors will facilitate both investigation of the ability of other carcinogens to intercalate into DNA and the synthesis of specific carcinogen-DNA adducts.

Original languageEnglish
Pages (from-to)9579-9584
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number18
DOIs
StatePublished - Sep 2 1997

Fingerprint

Dive into the research topics of 'An intercalation inhibitor altering the target selectivity of DNA damaging agents: Synthesis of site-specific aflatoxin B1 adducts in a p53 mutational hotspot'. Together they form a unique fingerprint.

Cite this