Human dietary exposures to aflatoxin B1 (AFB1) are a significant risk factor for developing hepatocellular carcinoma (HCC). Following oxidative bioactivation by microsomal P450 enzymes, AFB1 reacts with the N7-position of guanine, leading to formation of genotoxic AFB1-Fapy-dG adducts. In mice, AFB1 exposure is characterized by a unique mutational signature in liver tumor DNA, characterized by a preponderance of G to T mutations. This mutational signature is recapitulated in human HCC tumor DNA from individuals in areas with documented AFB1 contamination of the food supply. In principle, the characteristic AFB1 mutagenic signature in tumor DNA could result from (a) differences in reactivity of AFB1-exo-8,9-epoxide, (b) differences in repair efficiency of AFB1-Fapy-dG adducts, or (c) differences in mutagenic bypass of these lesions, in different DNA sequences, or some combination of each of these factors. For example, the thermodynamic stability of the AFB1-Fapy-dG adduct is modulated by the identity of the 5'-neighbor base pair. We have demonstrated that sequence-dependent stability differences in AFB1-modified DNA duplexes impact the repair efficiency by the hNEIL1-glycosylase. Kinetic analyses show an inverse correlation between the stability of the modified duplex and the NEIL1-catalyzed excision rates. AFB1-Fapy-dG adducts that form in poorly repaired sequences might lead to more frequent mutations as compared to those that form in easily-repaired sequences, thereby, influencing the mutational signature. Sequence-specific differences in AFB1-Fapy-dG adduct equilibria may differentially alter the recognition and repair of these lesions, as well as the mutagenic bypass, thus modulating the resulting mutagenic signature. In DNA, AFB1-Fapy-dG adducts equilibrate between multiple conformational and configurational isomers. The positions of these equilibria depend upon both DNA sequence and conformation. Of significance is the interconverting a- and b-anomers of AFB1-Fapy-dG adduct. If not repaired, the b- anomers are anticipated to be mutagenic, whereas the a-anomers may block replication, which may also influence the mutagenic spectrum.

Correlating the mutational signatures of the aflatoxin B1-Fapy-dG adduct with sequence-dependent DNA repair and adduct structure

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.