A Role for DNA Polymerase [beta] in Mutagenic UV Lesion Bypass

• Published in: The Journal of biological chemistry Vol. 277; no. 51; pp. 50046 - 50053
• Main Authors: Servant, L, Cazaux, C, Bieth, A, Iwai, S, Hanaoka, F, Hoffmann, J
• Format: Journal Article
• Language: English
• Published: 20.12.2002
• ISSN: 0021-9258

We report here that DNA polymerase [beta] (pol [beta]), 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 [beta] in UV-induced genetic instability, we analyzed the cellular and molecular effects of excess pol [beta]. We firstly demonstrated that mammalian cells overexpressing pol [beta] 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 [beta], we showed that CPD as well as, to a lesser extent, the thymine-thymine pyrimidine-pyrimidone (6-4) photoproduct, were bypassed. pol [beta] 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 [beta] in UV lesion bypass and suggest that deregulated pol [beta] may enhance UV-induced genetic instability.