Regulation of human DNA polymerase delta in the cellular responses to DNA damage.

The p12 subunit of polymerase delta (Pol delta) is degraded in response to DNA damage induced by UV, alkylating agents, oxidative, and replication stresses. This leads to the conversion of the Pol delta 4 holoenzyme to the heterotrimer, Pol delta 3. We review studies that establish that Pol delta 3 formation is an event that could have a major impact on cellular processes in genomic surveillance, DNA replication, and DNA repair. p12 degradation is dependent on the apical ataxia telangiectasia and Rad3 related (ATR) kinase and is mediated by the ubiquitinproteasome system. Pol delta 3 exhibits properties of an antimutator polymerase, suggesting that it could contribute to an increased surveillance against mutagenesis, for example, when Pol delta carries out bypass synthesis past small base lesions that engage in spurious base pairing. Chromatin immunoprecipitation analysis and examination of the spatiotemporal recruitment of Pol delta to sites of DNA damage show that Pol delta 3 is the primary form of Pol delta associated with cyclobutane pyrimidine dimer lesions and therefore should be considered as the operative form of Pol delta engaged in DNA repair. We propose a model for the switching of Pol delta with translesion polymerases, incorporating the salient features of the recently determined structure of monoubiquitinated proliferating cell nuclear antigen and emphasizing the role of Pol delta 3. Because of the critical role of Pol delta activity in DNA replication and repair, the formation of Pol delta 3 in response to DNA damage opens the prospect that pleiotropic effects may ensue. This opens the horizons for future exploration of how this novel response to DNA damage contributes to genomic stability. Mol. Mutagen. 2012. (c) 2012 Wiley Periodicals, Inc.