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Molecular mechanisms underlying aflatoxin‐induced mutagenesis
Author(s) -
Lin YingChih,
Li Liang,
Burgers Peter M.,
Stone Michael P.,
Lloyd R. Stephen
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb78
Subject(s) - aflatoxin , mutagenesis , mutagen , carcinogen , polymerase , carcinogenesis , biology , microbiology and biotechnology , dna , chemistry , mutation , genetics , gene , food science
Aflatoxin B 1 (AFB 1 ) 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 AFB 1 ‐DNA adducts, AFB 1 ‐N7‐Gua and AFB 1 ‐FAPY‐Gua, respectively. Both AFB 1 ‐N7‐Gua and AFB 1 ‐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 ξ 4 could bypass AFB 1 ‐N7‐Gua accurately, while the other two TLS polymerases κ and ξ were responsible for G to T mutations that were induced by AFB 1 ‐N7‐Gua and AFB 1 ‐FAPY. This work was supported by NIH R01 CA055678.