期刊
BIOCHEMISTRY
卷 50, 期 5, 页码 875-881出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi101717b
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资金
- RFBR [09-04-00869, 10-04-00809, 08-04-91109/CRDF RUB1-2919-MO-07]
- National Cancer Institute [CA099194]
Benzo[a]pyrene (B[a]P) is a well-characterized environmental polycyclic aromatic hydrocarbon pollutant. In living organisms, B[a]P is metabolized to the genotoxic anti-benzo[a]pyrene diol epoxide that reacts with cellular DNA to form stereoisomeric anti-B[a]PDE-N-2-dG adducts. In this study, we explored the effects of adduct stereochemistry and position in double-stranded DNA substrates on the functional characteristics of the catalytic domain of murine de novo DNA methyltransferase Dnmt3a (Dnmt3a-CD). A number of 18-mer duplexes containing site-specifically incorporated (+)- and (-)-trans-anti-B[a]PDE-N-2-dG lesions located 3'- and S'-adjacent to and opposite the target cytosine residue were prepared. Dnmt3a-CD binds cooperatively to the DNA duplexes with an up to 5-fold greater affinity compared to that for the undamaged DNA duplexes. Methylation assays showed a 1.7-6.3-fold decrease in the methylation reaction rates for the damaged duplexes. B[a]PDE modifications stimulated a nonproductive binding and markedly favored substrate inhibition of Dnmt3a-CD in a manner independent of DNA methylation status. The latter effect was sensitive to the position and stereochemistry of the B[a]PDE-N2-dG adducts. The overall effect of trans-anti-B[a]PDE-N-2-dG adducts on Dnmt3a-CD was less detrimental than in the case of the prokaryotic methyltransferases we previously investigated.
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