title: The K167I variant of DNA polymerase β that is found in Esophageal Carcinoma patients impairs polymerase activity and BER.
abstract: DNA polymerase β (pol β) is a key enzyme in DNA base excision repair, and an important factor for maintaining genomic integrity and stability. Esophageal carcinoma (EC) patients who have been identified as carrying the K167I variant of pol β have been shown to have decreased life expectancy. However, it is unknown if the variant affects pol β's functions and/or how it contributes to the initiation and progression of cancer. In this study, we expressed and purified the K167I variant. Moreover, we found that K167I significantly reduced polymerase activity. As a result, the K167I substitution reduced base excision repair (BER) efficiency when assayed in a reconstitution assay or when using cellular extracts. Finally, we observed EC cells expressing the K167I variant to be sensitive to DNA damaging agents. These results suggest the K167I variant affected pol β biochemical activity resulting in impaired BER function, which might subsequently contribute to genomic instability and cancer development.
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
authors.forename: Wenqiao
authors.initials: W
authors.lastname: Zang
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Du
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Chen
authors.affiliation: College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhao
mesh_terms: D000704:Analysis of Variance; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense
chemical_list: D018906:Antineoplastic Agents, Alkylating; D050505:Mutant Proteins; D004247:DNA; D008741:Methyl Methanesulfonate; D019951:DNA Polymerase beta