R152C DNA Pol β mutation impairs base excision repair and induces cellular transformation

// Ting Zhou 1, * , Feiyan Pan 1, * , Yan Cao 1, * , Ying Han 1, * , Jing Zhao 1 , Hongfang Sun 1 , Xiaolong Zhou 1 , Xuping Wu 3 , Lingfeng He 1 , Zhigang Hu 1 , Haoyan Chen 2 , Binghui Shen 4 , Zhigang Guo 1 1 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China 210023 2 Division of Gastroenterology and Hepatology, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China 200001 3 The Second Hospital of Nanjing, the Second Affiliated Hospital of Southeast University, Nanjing, China 210003 4 Department of Cancer Genetics and Epigenetics, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA 91010 * These authors have contributed equally to this work Correspondence to: Haoyan Chen, e-mail: chenhaoyan@gmail.com Binghui Shen, e-mail: bshen@coh.org Zhigang Guo, e-mail: guozgang@gmail.com Keywords: DNA polymerase β, BER, DNA damage, tumorigenesis, genome stability Received: September 05, 2015      Accepted: January 03, 2016      Published: January 8, 2016 ABSTRACT DNA polymerase β (Pol β) is a key enzyme in DNA base excision repair (BER), a pathway that maintains genome integrity and stability. Pol β mutations have been detected in various types of cancers, suggesting a possible linkage between Pol β mutations and cancer. However, it is not clear whether and how Pol β mutations cause cancer onset and progression. In the current work, we show that a substitution mutation, R152C, impairs Pol β polymerase activity and BER efficiency. Cells harboring Pol β R152C are sensitive to the DNA damaging agents methyl methanesulfonate (MMS) and H 2 O 2 . Moreover, the mutant cells display a high frequency of chromatid breakages and aneuploidy and also form foci. Taken together, our data indicate that Pol β R152C can drive cellular transformation.