title: Deregulated expression of DNA polymerase β is involved in the progression of genomic instability.
abstract: Deregulated expression of DNA polymerase beta (pol β) has been implicated in genomic instability that leads to tumorigenesis, yet the mechanisms underlying the pol β-mediated genetic instability remain elusive. In this study, we investigated the roles of deregulated expression of pol β in spontaneous and xenobiotic-induced genetic instability using mouse embryonic fibroblasts (MEFs) that express distinct pol β levels (wild-type, null, and overexpression) as a model system. Three genetic instability endpoints, DNA strand breaks, chromosome breakage, and gene mutation, were examined under various expression levels of pol β by comet assay, micronuclei test, and hprt mutation assay. Our results demonstrate that neither pol β deficiency nor pol β overexpression is sufficient for accumulation of spontaneous DNA damage that promotes a hyperproliferation phenotype. However, pol β null cells exhibit increased sensitivity to exogenous DNA damaging agents with increased genomic instability compared with pol β wild-type and overexpression cells. This finding suggests that a pol β deficiency may underlie genomic instability induced by exogenous DNA damaging agents. Interestingly, pol β overexpression cells exhibit less chromosomal or DNA damage, but display a higher hprt mutation frequency upon methyl methanesulfonate exposure compared with the other two cell types. Our results therefore indicate that an excessive amount of pol β may promote genomic instability, presumably through an error-prone repair response, although it enhances overall BER capacity for induced DNA damage.
authors.affiliation: Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Qingying
authors.initials: Q
authors.lastname: Luo
authors.forename: Yanhao
authors.initials: Y
authors.lastname: Lai
authors.forename: Shukun
authors.initials: S
authors.lastname: Liu
authors.forename: Mei
authors.initials: M
authors.lastname: Wu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Zunzhen
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D020552:Comet Assay; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D042822:Genomic Instability; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout
chemical_list: D007041:Hypoxanthine Phosphoribosyltransferase; D019951:DNA Polymerase beta