The role of polymorphisms of DNA polymerase beta in individual cancer susceptibility

DNA Polymerase β is the key gap-filling polymerase in base excision repair. Previous work has linked tumor-specific mutations in Pol β with cancer etiology, but little is known about the role of germline Pol β variants in human health. To determine the role of germline single amino acid substitutions on Pol β function, we started by analyzing the diversity at the POLB locus. Using this information, we focused on two germline substitutions, Pro242Arg and Arg137G1n, that were found at reasonable frequencies in specific populations on separate haplotypes.;We next conducted an in-depth study on these variants, using both biochemical and cell culture techniques. Purified proteins containing either amino acid substitution were found to be slow in vitro despite having right binding to gapped DNA. Expression of the 242Arg variant in culture increases genomic instability leading to cellular transformation. Upon treatment with a DNA alkylating agent, cells expressing 242Arg accumulated more double-strand breaks (DSBs) than cells expressing the ancestral 242Pro via both cell cycle independent and S-phase dependent mechanisms. Despite this accumulation of DNA damage, the overall survival of these cells was not affected. These findings suggest that these germline variants with aberrant polymerise activity may impact an individual's base excision repair capacity, potentially altering their cancer predisposition or response to chemotherapy. It would be interesting to study the effects of these variants in a DSB repair deficient background, or in mouse models where novel systemic phenotypes could be observed.