Deregulated expression of DNA polymerase β is involved in the progression of genomic instability

• Published in: Environmental and molecular mutagenesis Vol. 53; no. 5; pp. 325 - 333
• Main Authors: Luo, Qingying, Lai, Yanhao, Liu, Shukun, Wu, Mei, Liu, Yuan, Zhang, Zunzhen
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.06.2012; Wiley-Liss
• Subjects: Animals; base excision repair; Biological and medical sciences; Cell Cycle; Cells, Cultured; Comet Assay; Diverse techniques; DNA Damage; DNA damage and repair; DNA polymerase beta; DNA Polymerase beta - genetics; DNA Polymerase beta - metabolism; Fibroblasts - cytology; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Genomic Instability; Hypoxanthine Phosphoribosyltransferase - genetics; Medical sciences; Mice; Mice, Knockout; Molecular and cellular biology; Toxicology; Excision; Enzyme; Transferases; Genomics; base excision repair; Base; Chenopodiaceae; Beta; Nucleotidyltransferases; Toxicology; DNA damage and repair; Dicotyledones; DNA; Angiospermae; DNA polymerase beta; Genetics; Instability; Spermatophyta; Lesion; Repair; genomic instability; DNA-directed DNA polymerase
• ISSN: 0893-6692; 1098-2280
• DOI: 10.1002/em.21697

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. Environ. Mol. Mutagen. 2012. © 2012Wiley Periodicals, Inc.