A Role for DNA Polymerase β in Mutagenic UV Lesion Bypass

We report here that DNA polymerase β (pol β), the base excision repair polymerase, is highly expressed in human melanoma tissues, known to be associated with UV radiation exposure. To investigate the potential role of pol β in UV-induced genetic instability, we analyzed the cellular and molecular effects of excess pol β. We firstly demonstrated that mammalian cells overexpressing pol β are resistant and hypermutagenic after UV irradiation and that replicative extracts from these cells are able to catalyze complete translesion replication of a thymine-thymine cyclobutane pyrimidine dimer (CPD). By using in vitro primer extension reactions with purified pol β, we showed that CPD as well as, to a lesser extent, the thymine-thymine pyrimidine-pyrimidone (6-4) photoproduct, were bypassed. pol β mostly incorporates the correct dATP opposite the 3′-terminus of both CPD and the (6-4) photoproduct but can also misinsert dCTP at a frequency of 32 and 26%, respectively. In the case of CPD, efficient and error-prone extension of the correct dATP was found. These data support a biological role of pol β in UV lesion bypass and suggest that deregulated pol β may enhance UV-induced genetic instability.