title: Regulation of human DNA polymerase delta in the cellular responses to DNA damage.
abstract: The p12 subunit of polymerase delta (Pol δ) is degraded in response to DNA damage induced by UV, alkylating agents, oxidative, and replication stresses. This leads to the conversion of the Pol δ4 holoenzyme to the heterotrimer, Pol δ3. We review studies that establish that Pol δ3 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 ubiquitin-proteasome system. Pol δ3 exhibits properties of an "antimutator" polymerase, suggesting that it could contribute to an increased surveillance against mutagenesis, for example, when Pol δ 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 δ to sites of DNA damage show that Pol δ3 is the primary form of Pol δ associated with cyclobutane pyrimidine dimer lesions and therefore should be considered as the operative form of Pol δ engaged in DNA repair. We propose a model for the switching of Pol δ with translesion polymerases, incorporating the salient features of the recently determined structure of monoubiquitinated proliferating cell nuclear antigen and emphasizing the role of Pol δ3. Because of the critical role of Pol δ activity in DNA replication and repair, the formation of Pol δ3 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA. marietta_lee@NYMC.edu
authors.forename: Marietta Y W T
authors.initials: MY
authors.lastname: Lee
authors.forename: Sufang
authors.initials: S
authors.lastname: Zhang
authors.forename: Szu Hua Sharon
authors.initials: SH
authors.lastname: Lin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chea
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Wang
authors.forename: Christine
authors.initials: C
authors.lastname: LeRoy
authors.forename: Agnes
authors.initials: A
authors.lastname: Wong
authors.forename: Zhongtao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Ernest Y C
authors.initials: EY
authors.lastname: Lee
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D004249:DNA Damage; D004258:DNA Polymerase III / Q000378:metabolism*; D004261:DNA Replication; D006801:Humans; D010766:Phosphorylation; D014466:Ultraviolet Rays
chemical_list: D000477:Alkylating Agents; D004258:DNA Polymerase III