Molecular basis of aflatoxin-induced mutagenesis-role of the aflatoxin B1-formamidopyrimidine adduct

Aflatoxin B-1 (AFB(1)) is a known carcinogen associated with early-onset hepatocellular carcinoma (HCC) and is thought to contribute to over half a million new HCCs per year. Although some of the fundamental risk factors are established, the molecular basis of AFB(1)-induced mutagenesis in primate cells has not been rigorously investigated. To gain insights into genome instability that is produced as a result of replicating DNAs containing AFB(1) adducts, site-specific mutagenesis assays were used to establish the mutagenic potential of the persistent ring-opened AFB(1) adduct, AFB(1)-formamidopyrimidine (AFB(1)-FAPY). This lesion was highly mutagenic, yielding replication error frequencies of 97%, with the predominant base substitution being a G to T transversion. This transversion is consistent with previous mutational data derived from aflatoxin-associated HCCs. In vitro translesion synthesis assays demonstrated that polymerase (pol) zeta was the most likely candidate polymerase that is responsible for the G to T mutations induced by this adduct.