Kinetics of deamination and Cu(II)/H2O2/Ascorbate-induced formation of 5-methylcytosine glycol at CpG sites in duplex DNA.
Mutation in p53 tumor suppressor gene is a hallmark of human cancers. Six major mutational hotspots in p53 contain methylated CpG (mCpG) sites, and C -->T transition is the most common mutation at these sites. It was hypothesized that the formation of 5-methylcytosine glycol induced by reactive oxygen species, its spontaneous deamination to thymine glycol and the miscoding property of the latter may account, in part, for the ubiquitous C -->T mutation at CpG site. Here, we assessed the kinetics of deamination for two diastereomers of 5-methylcytosine glycol in duplex DNA. Our results revealed that the half-lives for the deamination of the (5S,6S) and (5R,6R) diastereomers of 5-methylcytosine glycol in duplex DNA at 37 degrees C were 37.4 +/- 1.6 and 27.4 +/- 1.0 h, respectively. The deamination rates were only slightly lower than those for the two diastereomers in mononucleosides. Next, we assessed the formation of 5-methyl-2'-deoxycytidine glycol in the form of its deaminated product, namely, thymidine glycol (Tg), in methyl-CpG-bearing duplex DNA treated with Cu(II)/H(2)O(2)/ascorbate. LC-MS/MS quantification results showed that the yield of Tg is similar as that of 5-(hydroxymethyl)-2'-deoxycytidine. Together, our data support that the formation and deamination of 5-methylcytosine glycol may contribute significantly to the C -->T transition mutation at mCpG dinucleotide site.
Cao
Huachuan
H
Department of Chemistry and Environmental Toxicology Graduate Program, University of California, Riverside, CA 92521-0403, USA.
Jiang
Yong
Y
Wang
Yinsheng
Y
D001205:Ascorbic Acid / Q000737:chemistry; D002853:Chromatography, Liquid; D003300:Copper / Q000737:chemistry; D018899:CpG Islands; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D003641:Deamination; D003854:Deoxyribonucleotides / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000737:chemistry; D007700:Kinetics; D053719:Tandem Mass Spectrometry; D013936:Thymidine / Q000031:analogs & derivatives / Q000737:chemistry
C545661:5-methylcytosine glycol; D003854:Deoxyribonucleotides; C029390:thymidine glycol; D003300:Copper; D003596:Cytosine; D004247:DNA; D006861:Hydrogen Peroxide; D001205:Ascorbic Acid; D013936:Thymidine
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