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• W4244178265 abstract "The long-term treatment of tamoxifen (TAM), widely used for adjuvant chemotherapy and chemoprevention for breast cancer, increases a risk of developing endometrial cancer. A high frequency of K-ras mutations has been observed in the endometrium of women treated with TAM. Human DNA polymerase (pol) η and pol κ are highly expressed in the reproductive organs and are associated with translesion synthesis past bulky DNA adducts. To explore the miscoding properties of α-(N2-deoxyguanosinyl)tamoxifen (dG-N2-TAM), a major TAM−DNA adduct, site-specifically modified oligodeoxynucleotides containing a single diastereoisomer of trans or cis forms of dG-N2-TAM were prepared by phosphoramidite chemical procedure and used as templates. The primer extension reaction catalyzed by pol κΔC, a truncated form of pol κ, extended more efficiently past the adduct than that of pol η by incorporating dCMP, a correct base, opposite the adduct. With pol η, all diastereoisomers of dG-N2-TAM promoted small amounts of direct incorporation of dAMP and deletions. With pol κΔC, dG-N2-TAM promoted small amounts of dTMP and/or dAMP incorporations and deletions. The miscoding properties varied depending on the diastereoisomer of dG-N2-TAM adducts and the DNA pol used. Steady-state kinetic studies were also performed using either the nonspecific sequence or the K-ras gene sequence containing a single dG-N2-TAM at the second base of codon 12. With pol η, the bypass frequency past the dA•dG-N2-TAM pair positioned in the K-ras sequence was only 2.3 times lower than that for the dC•dG-N2-TAM pair, indicating that dG-N2-TAM in the K-ras sequence has higher miscoding potential than that in the nonspecific sequence. However, with pol κΔC, the bypass frequency past the dC•dG-N2-TAM pair was higher than that of the dT•dG-N2-TAM pair in both sequences. The properties of pol η and pol κ are consistent with the mutagenic events attributed to TAM−DNA adducts." @default.
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• W4244178265 date "2006-09-07" @default.
• W4244178265 modified "2023-09-29" @default.
• W4244178265 title "Translesion Synthesis Past Tamoxifen-Derived DNA Adducts by Human DNA Polymerases η and κ" @default.
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• W4244178265 doi "https://doi.org/10.1021/bi0608461" @default.
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