Mutations associated with base excision repair deficiency and methylation-induced genotoxic stress.
The long-term effect of exposure to DNA alkylating agents is entwined with the cell's genetic capacity for DNA repair and appropriate DNA damage responses. A unique combination of environmental exposure and deficiency in these responses can lead to genomic instability; this "gene-environment interaction" paradigm is a theme for research on chronic disease etiology. In the present study, we used mouse embryonic fibroblasts with a gene deletion in the base excision repair (BER) enzymes DNA beta-polymerase (beta-pol) and alkyladenine DNA glycosylase (AAG), along with exposure to methyl methanesulfonate (MMS) to study mutagenesis as a function of a particular gene-environment interaction. The beta-pol null cells, defective in BER, exhibit a modest increase in spontaneous mutagenesis compared with wild-type cells. MMS exposure increases mutant frequency in beta-pol null cells, but not in isogenic wild-type cells; UV light exposure or N-methyl-N'-nitro-N-nitrosoguanidine exposure increases mutant frequency similarly in both cell lines. The MMS-induced increase in mutant frequency in beta-pol null cells appears to be caused by DNA lesions that are AAG substrates, because overexpression of AAG in beta-pol null cells eliminates the effect. In contrast, beta-pol/AAG double null cells are slightly more mutable than the beta-pol null cells after MMS exposure. These results illustrate that BER plays a role in protecting mouse embryonic fibroblast cells against methylation-induced mutations and characterize the effect of a particular combination of BER gene defect and environmental exposure.[1]References
- Mutations associated with base excision repair deficiency and methylation-induced genotoxic stress. Sobol, R.W., Watson, D.E., Nakamura, J., Yakes, F.M., Hou, E., Horton, J.K., Ladapo, J., Van Houten, B., Swenberg, J.A., Tindall, K.R., Samson, L.D., Wilson, S.H. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
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