Despite tamoxifen’s profound effects in controlling the growth of breast cancer, tamoxifen treatment has been associated with an increased incidence of endometrial cancer.  The basis for this carcinogenicity is believed to be caused by the formation of covalent adducts that arise from the reaction of metabolically activated tamoxifen derivatives and deoxyguanine of DNA.  The resulting four diastereoisomers of a-(N²-deoxyguanosyl)tamoxifen have demonstrated different  mutagenic properties. 

The objective of our research is to understand how the different stereoisomeric adducts affect lesion bypass by mutation-inducing polymerases.  We will determine if and how the error-prone polymerases, DNA polymerase IV and V of Escherichia coli, and the mammalian paralog of these enzymes, human DNA polymerase iota, replicate past these different isomers of tamoxifen-DNA adducts within a single sequence context.  This research will correlate structural stability of the adducts with lesion bypass activity by different polymerases.