Journal Article

The major, <i>N</i><sup>2</sup>-dG adduct of (+)-<i>anti</i>-B[a]PDE induces G→A mutations in a 5′-AGA-3′ sequence context

Rajiv Shukla, Nicholas E. Geacintov and Edward L. Loechler

in Carcinogenesis

Volume 20, issue 2, pages 261-268
Published in print February 1999 | ISSN: 0143-3334
Published online February 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.2.261
The major, N2-dG adduct of (+)-anti-B[a]PDE induces G→A mutations in a 5′-AGA-3′ sequence context

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Previously, in a random mutagenesis study, the (+)-anti diol epoxide of benzo[a]pyrene [(+)-anti-B[a]PDE] was shown to induce a complex mutational spectrum in the supF gene of an Escherichia coli plasmid, which included insertions, deletions and base substitution mutations, notably a significant fraction of GC→TA, GC→AT and GC→CG mutations. At some sites, a single type of mutation dominated and to understand individual mutagenic pathways these sites were chosen for study by site-specific means to determine whether the major adduct, [+ta]-B[a]P–N2-dG, was responsible. [+ta]-B[a]P–N2-dG was shown to induce ~95% G→T mutations in a 5′-TGC-3′ sequence context and ~80% G→A mutations in a 5′-CGT-3′ sequence context. (+)-anti-B[a]PDE induced principally GC→CG mutations in the G133 sequence context (5′-AGA-3′) in studies using both SOS-uninduced or SOS-induced E.coli. Herein, [+ta]-B[a]P–N2-dG is shown to induce principally G→A mutations (>90%) either without or with SOS induction in a closely related 5′-AGA-3′ sequence context (identical over 7 bp). This is the first time that there has been a discrepancy between the mutagenic specificity of (+)-anti-B[a]PDE versus [+ta]-B[a]P–N2-dG. Eight explanations for this discordance are considered. Four are ruled out; e.g. the second most prevalent adduct [+ca]-B[a]P–N2-dG also induces a preponderance of G→A mutations (>90%), so it also is not responsible for (+)-anti-B[a]PDE-induced G133→C mutations. The four explanations not ruled out are discussed and include that another minor adduct might be responsible and that the 5′-AGA-3′ sequence context differed slightly in the studies with [+ta]-B[a]P–N2-dG versus (+)-anti-B[a]PDE. In spite of the discordance, [+ta]-B[a]P–N2-dG induces G→A mutations in the context studied herein and this result has proven useful in generating a hypothesis for what conformations of [+ta]-B[a]P–N2-dG are responsible for G→T versus G→A mutations.

Keywords: (+)-anti-B[a]PDE, 7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; B[a]P, benzo[a]pyrene; GHD, gapped heteroduplex; MF, mutation frequency; O-G, 5′-TTTAG133AG131ACC-3′; PAH, polycyclic aromatic hydrocarbon.

Journal Article.  6603 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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