Impact of Benzo[a]pyrene-2'-deoxyguanosine Lesions On Methylation Of DNA by SssI and HhaI DNA Methyltransferases

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• 作者：Oksana M. Subach ; Vladimir B. Baskunov ; Maria V. Darii ; Diana V. Maltseva ; Dmitrii A. Alexandrov ; Olga V. Kirsanova ; Alexander Kolbanovskiy ; Marina Kolbanovskiy ; Francis Johnson ; Radha Bonala ; Nichola
• 刊名：Biochemistry
• 出版年：2006
• 出版时间：May 16, 2006
• 年：2006
• 卷：45
• 期：19
• 页码：6142 - 6159
• 全文大小：717K
• 年卷期：v.45,no.19(May 16, 2006)
• ISSN：1520-4995

文摘

DNA damage caused by the binding of the tumorigen 7R,8S-diol 9S,10R-epoxide (B[a]PDE),a metabolite of bezo[a]pyrene, to guanine in CpG dinucleotide sequences could affect DNA methylationand, thus, represent a potential epigenetic mechanism of chemical carcinogenesis. In this work, weinvestigated the impact of stereoisomeric (+)- and (-)-trans-anti-B[a]P-N²-dG adducts (B⁺ and B^-) onDNA methylation by prokaryotic DNA methyltransferases M.SssI and M.HhaI. These two methyltransferases recognize CpG and GCGC sequences, respectively, and transfer a methyl group to the C5 atomof cytosine (C). A series of 18-mer unmethylated or hemimethylated oligodeoxynucleotide duplexescontaining trans-anti-B[a]P-N²-dG adducts was generated. The B⁺ or B^- residues were introduced either5' or 3' adjacent or opposite to the target 2'-deoxycytidines. The B[a]PDE lesions practically produced noeffect on M.SssI binding to DNA but reduced M.HhaI binding by 1-2 orders of magnitude. In mostcases, the benzo[a]pyrenyl residues decreased the methylation efficiency of hemimethylated andunmethylated DNA by M.SssI and M.HhaI. An absence of the methylation of hemimethylated duplexeswas observed when either the (+)- or the (-)-trans-anti-B[a]P-N²-dG adduct was positioned 5' to thetarget dC. The effects observed may be related to the minor groove conformation of the bulky benzo[a]pyrenyl residue and to a perturbation of the normal contacts of the methyltransferase catalytic loop withthe B[a]PDE-modified DNA. Our results indicate that a trans-anti-B[a]P-N²-dG lesion flanking a targetdC in the CpG dinucleotide sequence on its 5'-side has a greater adverse impact on methylation than thesame lesion when it is 3' adjacent or opposite to the target dC.