Are 8-oxoguanine (8-oxoGua) and 5-hydroxymethyluracil (5-hmUra) oxidatively damaged DNA bases or transcription (epigenetic) marks?

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• 作者：Ewelina Zarakowska ; Daniel Gackowski ; Marek Foksinski ; Ryszard Olinski ; ^{ryszardo@cm.umk.pl" class="auth_mail}
• 关键词：8-oxoGua ; 8-oxoguanine ; 8-oxodG ; 8-oxo-7 ; 8-dihydro-2&prime ; -deoxyguanosine ; 5-hmUra ; 5-hydroxymethyluracil ; 5-hmdU ; 5-hydroxymethyl-2&prime ; -deoxyuridine ; 5-hmCyt ; 5-hydroxymethylcytosine ; 5-hmdC ; 5-hydroxymethyl-2&prime ; -deoxycytidine ; 5-mCyt ; 5-methylcytosine ; 5-mdC ; 5-methyl-2&prime ; -deoxycytidine ; S-cdA ; (5&prime ; S)-8 ; 5&prime ; -cyclo-2&prime ; -deoxyadenosine ; AID ; activation-induced cytidine deaminase ; TETs (TET proteins) ; ten-eleven translocation proteins ; OGG1 ; 8-oxoguanine glycosylase ; TDG
• 刊名：Mutation Research/Genetic Toxicology and Environmental Mutagenesis
• 出版年：April, 2014
• 年：2014
• 卷：764-765
• 期：Complete
• 页码：58-63
• 全文大小：780 K

文摘

The oxidatively modified DNA base 8-oxo-7,8-dihydroguanine (8-oxoGua) is nontoxic and weakly mutagenic. Here we report on new data suggesting a potential for 8-oxoGua to affect the expression of several genes via epigenetic changes resulting in chromatin relaxation. Using pig thymus extract, we analyzed the distribution of 8-oxoGua among different nuclei fractions representative of transcriptionally active and silenced regions. The levels of 8-oxo-7,8-dihydro-2鈥?deoxyguanosine (8-oxodG) found in transcriptionally active euchromatin (4.37/10⁶ nucleotides) and in the matrix fraction (4.16/10⁶ nucleotides) were about 5 times higher than in transcriptionally silenced heterochromatin (0.91/10⁶ nucleotides). Other experimental data are presented which suggest that 8-oxoGua present in specific DNA sequences may be widely used for transcription regulation.

Like 8-oxoGua, 5-hydroxymethyluracil (5-hmUra) is another oxidatively modified DNA base (the derivative is formed by thymine oxidation). Recent experimental evidence supports the notion that 5-hmUra plays an important role in active DNA demethylation. This involves overexpression of activation-induced cytidine deaminase (AID) and ten-eleven translocation 1 (TET1) protein (the key proteins involved in active demethylation), which leads to global accumulation of 5-hmUra. Our preliminary data demonstrate a significant increase of the 5-hmUra levels in pig brain extract when compared with liver extract. The lack of 5-hmUra in Escherichia coli DNA also speaks for a role of this modification in the active demethylation process. It is concluded that 8-oxodG and 5-hmUra in DNA may be considered as epigenetic marks.