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. 1991 Dec;129(4):981–989. doi: 10.1093/genetics/129.4.981

Specificity of Base Substitutions Induced by the Acridine Mutagen Icr-191: Mispairing by Guanine N7 Adducts as a Mutagenic Mechanism

S R Sahasrabudhe 1, X Luo 1, M Z Humayun 1
PMCID: PMC1204782  PMID: 1783299

Abstract

As the most nucleophilic site in DNA, the guanine N7 atom is a major site of adduction by a large number of alkylating mutagens and carcinogens. Aflatoxin B(1), a powerful mutagen, is believed to act through its reaction with this DNA site. On the basis of the specificity of base substitutions induced by various adduct forms of aflatoxin, we have proposed that bulky guanine N7 adducts elicit base substitutions by two mechanisms. The first mechanism is similar to that observed for a number of bulky noninstructive lesions, whereas the second mechanism invokes mispairing between N7-adducted guanine and thymine. A prediction of the mispairing hypothesis is that diverse bulky guanine N7 adducts (regardless of structural similarities with the aflatoxins) should induce predominantly G-to-A transitions. Accordingly, we have recently observed that base substitutions induced by the acridine half-mustard ICR-191 in the M13 double-stranded DNA transfection system are predominantly G:C-to-A:T transitions. Here, by transfecting ICR-191-treated M13 AB28 single-stranded DNA into Escherichia coli, we show that base substitutions are predominantly targeted to guanines. Since the N7-adducted-guanine:thymine mispairing is proposed to require N1 deprotonation promoted by the primary N7 lesion, guanine imidazole ring-opening should abolish this mispairing property, and thereby alter the specificity of mutagenesis. Here, we show that the incubation of ICR-191-treated RF DNA at pH 10.5 results in a significant reversal of the specificity of G:C-targeted substitutions such that G-to-T transversions predominated over G-to-A transitions. These data suggest that the ring-opened forms may be processed as classical noninstructional lesions as previously deduced for ring-opened aflatoxin-guanine lesions. These findings raise the intriguing possibility that mispairing by guanine N7 adducts may be a source of induced as well as background mutagenesis.

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Selected References

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