Overexpression of DNA polymerase β results in an increased rate of frameshift mutations during base excision repair

Abstract

DNA polymerase β (Pol β) is important for the base excision repair (BER) pathway. Overexpression of Pol β is frequently found in cancer cells and is thought to be associated with tumorigenesis. In this study, we examined BER fidelity in extracts derived from a human lymphoblastoid cell line that overexpresses Pol β compared to normal control cells. Using an in vitro mutagenesis assay, we found an increased rate of frameshift mutations arising during DNA repair in whole-cell extracts derived from the Pol β-overexpressing cells. We demonstrate that the addition of excess Pol β to a control cell extract enhances the mutagenic potential of the extract. Furthermore, using cell extracts and purified Pol β, we demonstrate that the mechanism of frameshift formation involves slippage of Pol β during the one-nucleotide gap-filling step of BER and that this slippage is fixed by strand-displacement synthesis stimulated by an excess of Pol β. © The Author 2007. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved.