title: Molecular basis of aflatoxin-induced mutagenesis-role of the aflatoxin B1-formamidopyrimidine adduct.
abstract: 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.
authors.affiliation: Oregon Institute of Occupational Health Sciences and Cancer Biology Program, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Ying-Chih
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA and.
authors.forename: Alena V
authors.initials: AV
authors.lastname: Makarova
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA and.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Burgers
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Stone
authors.affiliation: Oregon Institute of Occupational Health Sciences and Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA lloydst@ohsu.edu.
authors.forename: R Stephen
authors.initials: RS
authors.lastname: Lloyd
mesh_terms: D016604:Aflatoxin B1 / Q000009:adverse effects*; D000818:Animals; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D002522:Chlorocebus aethiops; D018736:DNA Adducts / Q000009:adverse effects*; D004261:DNA Replication / Q000235:genetics*; D004277:DNA, Single-Stranded / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000009:adverse effects*
chemical_list: D018736:DNA Adducts; D004277:DNA, Single-Stranded; D011743:Pyrimidines; C061392:aflatoxin B1-formamidopyrimidine; D016604:Aflatoxin B1