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Biochemical basis of genotoxicity of heterocyclic arylamine food mutagens: Human DNA polymerase η selectively produces a two-base deletion in copying the N2-guanyl adduct of 2-amino-3-methylimidazo[4,5-f]quinoline but not the C8 adduct at the NarI G3 site
- Biochemical basis of genotoxicity of heterocyclic arylamine food mutagens: Human DNA polymerase η selectively produces a two-base deletion in copying the N2-guanyl adduct of 2-amino-3-methylimidazo[4,5-f]quinoline but not the C8 adduct at the NarI G3 site
- Choi J.-Y.; Stover J.S.; Angel K.C.; Chowdhury G.; Rizzo C.J.; Guengerich F.P.
- Ewha Authors
- Issue Date
- Journal Title
- Journal of Biological Chemistry
- Journal of Biological Chemistry vol. 281, no. 35, pp. 25297 - 25306
- SCI; SCIE; SCOPUS
- Document Type
- Heterocyclic arylamines are highly mutagenic and cause tumors in animal models. The mutagenicity is attributed to the C8- and N2-G adducts, the latter of which accumulates due to slower repair. The C 8- and N2-G adducts derived from 2-amino-3- methylimidazo[4,5-f ]quinoline (IQ) were placed at the G1 and G 3 sites of the NarI sequence, in which the G3 site is an established hot spot for frameshift mutation with the model arylamine derivative 2-acetylaminofluorene but G1 is not. Human DNA polymerase (pol) η extended primers beyond template G-IQ adducts better than did pol κ and much better than pol ι or δ. In 1-base incorporation studies, pol η inserted C and A, pol ι inserted T, and pol κ inserted G. Steady-state kinetic parameters were measured for these dNTPs opposite the C8- and N2-IQ adducts at both sites, being most favorable for pol η. Mass spectrometry of pol η extension products revealed a single major product in each of four cases; with the G1 and G 3 C8-IQ adducts, incorporation was largely error-free. With the G3 N2-IQ adduct, a -2 deletion occurred at the site of the adduct. With the G1 N2-IQ adduct, the product was error-free at the site opposite the base and then stalled. Thus, the pol η products yielded frameshifts with the N2 but not the C 8 IQ adducts. We show a role for pol η and the complexity of different chemical adducts of IQ, DNA position, and DNA polymerases. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
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