Nearest neighbor effects on carcinogen binding to guanine runs in DNA

Abstract

A synthetic DNA fragment was constructed to determine the effect of 5' and 3' neighbors of guanine runs on the binding of chemical carcinogens. Determinations were made on the relative intensity of reactivity between aflatoxin B1 or benzo(a)pyrene and methylnitrosourea or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with various guanine positions in an endlabeled DNA fragment of known sequence. After reaction, the fragments were depurinated to produce strand breaks to allow Maxam and Gilbert sequencing for guanine positions. Relative reaction intensities were compared densitometrically. 3' neighbors exerted greater influence on carcinogen binding than did 5' neighbors, the influence extended only to the adjacent guanine and depended upon the chemical nature of the carcinogen. In addition, the presence of one carcinogen adduct in the guanine run influenced the formation of a subsequent adduct when the DNA was exposed to a second carcinogen, and this effect also depended on the nature of the second carcinogen. The results suggest that DNA adduct formation in the presence of multiple carcinogens is more complicated than an additive mechanism would suggest.

Treatment of Human Cells with N-Nitroso(acetoxymethyl)methylamine: Distribution Patterns of Piperidine-Sensitive DNA Damage at the Nucleotide Level of Resolution Are Related to the Sequence Context

“…We observed that DNA damage induced by MNU or NDMAOAc is sequence-specific in a run of three or more guanines in purified DNA and in cellular DNA ( Figure 5). Our results, and those realized by other investigators, confirm that the sequence specificities of S N 1 agents are different from those of S N 2 agents ( Figure 5) (12)(13)(14)(15)33). S N 1 methylating agents (MNU and NDMAOAc) preferentially methylate the central guanines in a run of three or more guanines.…”

Formation of Cyclobutane Thymine Dimers from UVA Photosensitization of Pyridopsoralen Monoadducted DNA

“…has no influence on photosensitized dimerization at site c. This study shows, for the first time, that one lesion can induce the formation of a second different lesion. A "neighbor effect" has already been observed for carcinogen bound to guanine runs in DNA (25). However, the phenomenon is somewhat different because the first carcinogen bound to DNA modifies the specificity of subsequent binding by a second molecule of carcinogen but does not induce a new type of lesion.…”

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

“…Very few studies thus far have focused on differential selectivity of specic base sequences. 64 Jernstroem, et al suggest that guanines adjacent to or anked by guanines are more reactive [62][63][64][65][66] In contradiction, other studies predict that guanines anked by pyrimidine bases are more reactive due to less steric effects as compared to guanines anked by purine bases. 56,[67][68][69] The reactive site of codon 248 in our 32 bp fragment is a guanine anked by guanine, while codons 244 and 243 are guanines anked by purine on one side and pyrimidine on the other side and show intermediate reactivity.…”