Solution Conformation of the (-)-trans-anti-Benzo[c]phenanthrene-dA ([BPh]dA) Adduct opposite dT in a DNA Duplex: Intercalation of the Covalently Attached Benzo[c]phenanthrenyl Ring to the 3'-Side of the Adduct Site and Comparison with the (+)-trans-anti-[BPh]dA opposite dT Stereoisomer

Monique Cosman, Alfred Laryea, Radovan Fiala, Brian E. Hingerty, Shantu Amin, Nicholas E. Geacintov, Suse Broyde, Dinshaw J. Patel

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Abstract

This paper reports on NMR-molecular mechanics structural studies of the (-)-trans-antibenzo[c]phenanthrene-dA adduct positioned opposite dT in the sequence context of the d(Cl-T2-C3-T4-C5-[BPh]A6-C7-T8-T9-C10-C11)•d(G12-G13-A14-A15-G16-T17-G18-A19-G20-A21-G22) duplex (designated as the (-)-trans-anti-[BPh]dA'dT 11-mer duplex). This adduct is derived from the covalent binding of (-)-1,2-dihydroxy-3,4-epoxy-l, 2,3,4-tetrahydro-benzo[c]phenanthrene [(-)-anti-BPhDE] to N6 of dA6 in this duplex sequence. The benzo[c]phenanthrenyl and nucleic acid exchangeable and nonexchangeable protons were assigned in the predominant conformation following analysis of two-dimensional NMR data sets in H2O and D2O buffer solution. The solution structure of the (-)-trans-anti-[BPh]dA•dT linter duplex has been determined by incorporating intramolecular and carcinogen-DNA proton-proton distances defined by lower and upper bounds deduced from NOESY data sets as restraints in molecular mechanics computations in torsion angle space. The results show that the [BPh]dA6•dT17 base pair propeller twists and buckles slightly to permit the covalently attached benzo[c]phenanthrenyl ring to intercalate between the [BPh]dA6•dT17 and dC7•dG16 base pairs to the 3'-side of the [BPh]dA6 lesion site without disrupting the Watson-Crick hydrogen bond alignments in the modified duplex. The strain in the highly sterically hindered fjord region of the benzo[c]phenanthrenyl moiety is relieved by the propeller-like nonplanar geometry of the aromatic phenanthrenyl ring system, which stacks predominantly with the dG16 and dT17 bases on the unmodified strand. The benzylic ring adopts a distorted half-chair form, in which the HI and H2 protons are pseudo-diequatorial and the H3 and H4 protons are pseudodiaxial. The current observation that the (-)-trans-anti-[BPh]dA positioned opposite dT intercalates to the 3'-side of the intact modified base pair contrasts with our previous demonstration that the stereoisomeric (+)-trans-anti-[BPh]dA adduct positioned opposite dT intercalates to the 5'-side of the intact modified base pair [Cosman, M., et al. (1993b) Biochemistry 32, 12488-12497]. These stereochemically induced structural differences between isomeric [BPh]dA lesions derived from the binding of chiral (+)- and (-)-anti-BPhDE enantiomers may in turn profoundly influence the interactions of the carcinogen-modified DNA with repair and replication enzymes in the cell.

Original languageEnglish (US)
Pages (from-to)1295-1307
Number of pages13
JournalBiochemistry
Volume34
Issue number4
DOIs
StatePublished - Jan 1995

All Science Journal Classification (ASJC) codes

  • Biochemistry

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