Altered DNA Polymerase Expression in Breast Cancer Cells Leads to a Reduction in DNA Replication Fidelity and a Higher Rate of Mutagenesis

The recently discovered human enzyme DNA polymerase (pol ) has been shown to have an exceptionally high error rate on artificial DNA templates. Although there is a considerable body of in vitro evidence for a role for pol in DNA lesion bypass, there is no in vivo evidence to confirm this action. We report here that pol expression is elevated in breast cancer cells and correlates with a significant decrease in DNA replication fidelity. We also demonstrate that UV treatment of breast cancer cells additionally increases pol expression with a peak occurring between 30 min and 2 h after cellular insult. This implies that the change in pol expression is an early event after UV-mediated DNA damage. That pol may play a role in the higher mutation frequencies observed in breast cancer cells was suggested when a reduction in mutation frequency was found after pol was immunodepleted from nuclear extracts of the cells. Analysis of the UV-induced mutation spectra revealed that >90% were point mutations. The analysis also demonstrated a decreased C3T nucleotide transition and an increased C3A transversion rate. Overall, our data strongly suggest that pol may be involved in the generation of both increased spontaneous and translesion mutations during DNA replication in breast cancer cells, thereby contributing to the accumulation of genetic damage.