The major, N2-dG adduct of (+)-anti-B[a]PDE shows a dramatically different mutagenic specificity (predominantly, G → a) in a 5'-CGT-3' sequence context

Rajiv Shukla, Tongming Liu, Nicholas E. Geacintov, Edward L. Loechler

Research output: Contribution to journalArticle

Abstract

Mutations induced by the (+)-anti diol epoxide of benzo[a]pyrene [(+)- anti-B[a]PDE] were described previously in the supF gene of the Escherichia coli plasmid pUB3 [Rodriguez et al. (1993) Biochemistry, 32. 1759]. (+)- anti-B[a]PDE induced a complex pattern of mutations, including insertions, deletions, frameshifts, as well as base substitution mutations, which for G:C base pairs alone included a significant fraction of G:C → T:A, A:T and C:G mutations. A variety of results suggest that most of these mutations arise from the major adduct [[+ta]-B[a]P-N2-dG), raising the question how can a single adduct induce different kinds of mutations? Our working hypothesis in this regard is that (1) an adduct can adopt multiple conformations; (2) different conformations cause different mutations; and (3) adduct conformation is controlled by various factors, such as DNA sequence context. To investigate what conformation is associated with what mutation, it is essential to find examples where [+ta]-B[a]P-N2-dG induces principally one kind of mutation as a prelude to the study in that same context of the conformation(s) potentially relevant to mutagenesis. Earlier work indicated that (+)-anti-B[a]PDE gave a preponderance of G → A mutations in a 5'-CGT-3 sequence context, and herein it is shown that these mutations are likely to be attributable to the major adduct, since in this same sequence context [+ta]-B[a]P-N2-dG studied site specifically also induces principally G → A mutations (~82%). Previously, [+ta]-B[a]P-N2-dG was shown to induce principally G → T mutations (~97%) in a 5'-TGC-3' sequence context. Thus, by simply altering its surrounding sequence context this adduct can give a preponderance of either G → A or G → T mutations. This is the most dramatic change in base substitution mutagenic specificity for an adduct described to date and illustrates that the qualitative pattern of mutagenesis by a bulky adduct can be remarkably diverse.

Original languageEnglish (US)
Pages (from-to)10256-10261
Number of pages6
JournalBiochemistry
Volume36
Issue number33
DOIs
StatePublished - Aug 19 1997

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ASJC Scopus subject areas

  • Biochemistry

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