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

Lin YC, Li L, Makarova AV, Burgers PM, Stone MP, Lloyd RS
Carcinogenesis. 2014 35 (7): 1461-8

PMID: 24398669 · PMCID: PMC4076807 · DOI:10.1093/carcin/bgu003

Aflatoxin B1 (AFB1) 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 AFB1-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 AFB1 adducts, site-specific mutagenesis assays were used to establish the mutagenic potential of the persistent ring-opened AFB1 adduct, AFB1-formamidopyrimidine (AFB1-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) ζ was the most likely candidate polymerase that is responsible for the G to T mutations induced by this adduct.

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MeSH Terms (14)

Aflatoxin B1 Animals Carcinoma, Hepatocellular Chlorocebus aethiops COS Cells DNA, Single-Stranded DNA Adducts DNA Replication Humans Liver Neoplasms Mutagenesis, Site-Directed Mutation Polymerase Chain Reaction Pyrimidines

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