Base-sequence dependence of covalent binding of benzo[a]pyrenediol epoxide to guanine in oligodeoxyribonucleotides

Abstract

The base-sequence dependence of the yield of the covalent binding reaction of (+)-anti-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE] with the exocyclic amino group of guanine surrounded by different flanking bases X and Y in the single-stranded oligonucleotide d(CTATXGYTATC) was investigated. With an initial ratio of [(+)-anti-BPDE]/[oligonucleotide strand] = 2, the percentage of modified strands varied from 20 +/- 2% when the modified dG was surrounded by pyrimidines to 5-7% when the central dG was surrounded by purines. The trans/cis ratio of (+)-anti-BPDE-N2-dG adducts was in the range of 3-5. The lower reaction yields observed when the modified guanine residues in single-stranded oligonucleotides are surrounded by purines rather than by pyrimidines is tentatively attributed (1) to steric effects arising from the presence of the bulkier purines flanking the reacting dG moieties on the 5'- and 3'-sides and/or (2) to noncovalent interactions between anti-BPDE and neighboring purines which decrease the probability of optimal alignment for covalent binding between the interacting moieties in the bimolecular transition-state complex. Noncovalent intercalation of (+)-anti-BPDE prior to the covalent binding reaction is not a relevant process in the case of single-stranded oligonucleotides and is therefore not a critical requirement for obtaining high yields of covalent trans- and cis-(+)-anti-BPDE-N2-dG adducts in these oligonucleotide sequences.

Base sequence selectivity in the binding of 7(R),8(S)-dihydroxy-9(S),10(R)-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene to oligodeoxyribonucleotide duplexes

“…There was a preference for binding to the guanine bases of codon 12 (GGA) over many of the other guanines present. In a study of the reaction of (+) -anti-BPDE with single-stranded oligodeoxyribonucleotides, Margulis et al (33) found higher reactivity for dGs surrounded by pyrimidines than for dGs surrounded by purines, a result consistent with our finding of highest reactivity for CGC in double-stranded oligodeoxyribonucleotides. As in the present study, Osborne (16) found that deoxyguanosines that had a neighboring dG reacted more extensively than dGs that did not (16).…”

Chemical selectivity of nucleobase adduction relative to in vivo mutation sites on exon 7 fragment of p53 tumor suppressor gene

“… 64 Jernstroem, et al suggest that guanines adjacent to or flanked by guanines are more reactive 62 – 66 In contradiction, other studies predict that guanines flanked by pyrimidine bases are more reactive due to less steric effects as compared to guanines flanked by purine bases. 56 , 67 – 69 The reactive site of codon 248 in our 32 bp fragment is a guanine flanked by guanine, while codons 244 and 243 are guanines flanked by purine on one side and pyrimidine on the other side and show intermediate reactivity. Codon adduction sites in ss-DNA oligonucleotides are guanines sandwiched between one purine and one pyrimidine.…”

Effect of DNA Base Sequence on the Configuration of Deoxyadenosine Adducts Formed by the Fjord Region Diol Epoxide, (+)-(1R,2S,3R,4S)-3,4-Dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene

“…The sequence of the DNA target plays a role in determining the extent of diol epoxide adduct formation in DNA (Boles & Hogan, 1985;Reardon et al, 1989;Kootstra et al, 1989;Rill & Marsch, 1990;Dittrich & Krugh, 1991a,b;Ross et al, 1993;Margulis et al, 1993;Schwartz et al, 1994). The next question is whether sequence affects the types of adducts that are formed, which themselves may have different biological effects.…”