Evidence suggests that oxidative damage to cells can generate the mutagenic 7,8-dihydro-8-oxo-2’-deoxyguanosine (8oxodG). 8oxodG can be formed as a nucleic acid already incorporated into DNA or as part of the nucleotide pool that exists to provide nucleotides for incorporation into DNA. When integrated into DNA, 8oxodG can cause G to T transversion mutations and as such, it has been implicated in carcinogenesis. When we treat MCF-7 breast cancer cells with 8oxodG we find that cells take up 8oxodG and incorporate it into their DNA. Nucleotides that are incorporated must exist in the dNTP form and thus, this indicates that 8oxodG is taken into the cell and phosphorylated into the 8oxodGTP form. We also show that the incorporation of 8oxodG is less in the presence of 17Β-estradiol. Our studies indicate that 17Β-estradiol is able to increase the levels of Mth1 in MCF-7 cells. Mth1 is a homologue of the MutT enzyme in E. coli and is known to be able to convert 8oxodGTP into 8oxodGMP, preventing its incorporation into DNA. Mth1 therefore acts as a preventative mechanism against mutation. This suggests that the reduced incorporation of 8oxodG into cells is at least partially due to the activity of Mth1.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]