title: Mutation of DNA Polymerase β R137Q Results in Retarded Embryo Development Due to Impaired DNA Base Excision Repair in Mice.
abstract: DNA polymerase β (Pol β), a key enzyme in the DNA base excision repair (BER) pathway, is pivotal in maintaining the integrity and stability of genomes. One Pol β mutation that has been identified in tumors, R137Q (arginine to glutamine substitution), has been shown to lower polymerase activity, and impair its DNA repair capacity. However, the exact functional deficiency associated with this polymorphism in living organisms is still unknown. Here, we constructed Pol β R137Q knock-in mice, and found that homozygous knock-in mouse embryos were typically small in size and had a high mortality rate (21%). These embryonic abnormalities were caused by slow cell proliferation and increased apoptosis. In R137Q knock-in mouse embryos, the BER efficiency was severely impaired, which subsequently resulted in double-strand breaks (DSBs) and chromosomal aberrations. Furthermore, R137Q mouse embryo fibroblasts (MEFs) were more sensitive to DNA-damaging reagents, such as methyl methanesulfonate (MMS) and H2O2. They displayed a higher percentage of DSBs, and were more likely to undergo apoptosis. Our results indicate that R137 is a key amino acid site that is essential for proper Pol β functioning in maintaining genomic stability and embryo development.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
authors.forename: Feiyan
authors.initials: F
authors.lastname: Pan
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: The Second Hospital of Nanjing, The Second Affiliated Hospital of Southeast University, 1-1 Zhongfu Road, Nanjing, 210003, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Kuang
authors.affiliation: Departments of Radiation Biology and Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, 91010, USA.
authors.forename: Huifang
authors.initials: H
authors.lastname: Dai
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
authors.forename: Hongfang
authors.initials: H
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: The Second Hospital of Nanjing, The Second Affiliated Hospital of Southeast University, 1-1 Zhongfu Road, Nanjing, 210003, China.
authors.forename: Xuping
authors.initials: X
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
authors.forename: Lingfeng
authors.initials: L
authors.lastname: He
authors.affiliation: Departments of Radiation Biology and Molecular Medicine, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, 91010, USA.
authors.forename: Binghui
authors.initials: B
authors.lastname: Shen
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Guo