Abstract
Abstract Aflatoxin B1 (AFB1) is a known mutagen and carcinogen that is associated with hepatocellular carcinoma (HCC). Although the underlying mechanisms contributing to these events are far from complete, our investigations provide insight into the molecular mechanisms of aflatoxin‐accelerated carcinogenesis. Site‐specific mutagenesis assays in primate cells were used to examine the mutagenic potential of the primary and persistent AFB1‐DNA adducts, AFB1‐N7‐Gua and AFB1‐FAPY‐Gua, respectively. Both AFB1‐N7‐Gua and AFB1‐FAPY were highly mutagenic at frequencies of 45% and 97%, respectively, with the predominant base substitution being G to T transversions, a mutation that is consistent with observations made in aflatoxin‐associated HCC samples. Moreover, we present the first biochemical evidence that the replicative polymerase δ and the specialized translesion synthesis (TLS) polymerase ξ4 could bypass AFB1‐N7‐Gua accurately, while the other two TLS polymerases κ and ξ were responsible for G to T mutations that were induced by AFB1‐N7‐Gua and AFB1‐FAPY.This work was supported by NIH R01 CA055678.
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