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.
Highlights
DNA Polymerase b (Pol b) is the main polymerase involved in the base excision repair pathway (BER), the pathway responsible for repairing up to 20,000 endogenous lesions per cell per day [1,2]
This polymorphism is one of two in the POLB gene that results in a missense mutation and the allele with the rs3136797 single nucleotide polymorphisms (SNPs) encodes the P242R Pol b protein
This allele was shown to be evolutionarily distinct from other POLB SNPs studied and its low frequency suggests that few homozygotes exist
Summary
DNA Polymerase b (Pol b) is the main polymerase involved in the base excision repair pathway (BER), the pathway responsible for repairing up to 20,000 endogenous lesions per cell per day [1,2]. Little is known about the biochemical and cellular characteristics of the rs3136707 SNP, in which the proline at residue 242 is altered to arginine (P242R) or its role in human health. Carriers of this allele include populations from Eastern Europe [6]. Patients heterozygous for this allele exhibited decreased survival when treated for either lung cancer or lymphoma [9,10] This residue is located at the base of Loop II, a region that has been shown by us to be critical for polymerase activity and fidelity [11,12,13]
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