title: A germline polymorphism of DNA polymerase beta induces genomic instability and cellular transformation.
abstract: Several germline single nucleotide polymorphisms (SNPs) have been identified in the POLB gene, but little is known about their cellular and biochemical impact. DNA Polymerase β (Pol β), encoded by the POLB gene, is the main gap-filling polymerase involved in base excision repair (BER), a pathway that protects the genome from the consequences of oxidative DNA damage. In this study we tested the hypothesis that expression of the POLB germline coding SNP (rs3136797) in mammalian cells could induce a cancerous phenotype. Expression of this SNP in both human and mouse cells induced double-strand breaks, chromosomal aberrations, and cellular transformation. Following treatment with an alkylating agent, cells expressing this coding SNP accumulated BER intermediate substrates, including single-strand and double-strand breaks. The rs3136797 SNP encodes the P242R variant Pol β protein and biochemical analysis showed that P242R protein had a slower catalytic rate than WT, although P242R binds DNA similarly to WT. Our results suggest that people who carry the rs3136797 germline SNP may be at an increased risk for cancer susceptibility.
authors.affiliation: Departments of Therapeutic Radiology and Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yamtich
authors.forename: Antonia A
authors.initials: AA
authors.lastname: Nemec
authors.forename: Agnes
authors.initials: A
authors.lastname: Keh
authors.forename: Joann B
authors.initials: JB
authors.lastname: Sweasy
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage / Q000235:genetics; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D004198:Disease Susceptibility; D005786:Gene Expression Regulation; D042822:Genomic Instability / Q000235:genetics*; D005854:Germ Cells; D006801:Humans; D051379:Mice; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D019951:DNA Polymerase beta