The S180R Human Germline Variant of DNA Polymerase β Exhibits Low Fidelity and the Potential to Drive Cancer Formation

Abstract

DNA polymerase β (Pol β) is an important repair polymerase that lacks proofreading capacity. It is estimated to function in the repair of up to 50,000 DNA lesions per cell per day, playing an important role within the short patch base excision repair pathway (SP-BER). Given the significant role Pol β plays in repairing DNA, genetic variants of Pol β have the potential to perturb repair and allow for mutation accumulation which can potentiate cancer formation. Here we have discovered a novel human germline variant of Pol β (S180R) which introduces a significant residue mutation within the dNTP binding pocket. We have shown that this S180R variant demonstrates a mutator phenotype due to its loss of ability to discriminate correct nucleotides from incorrect nucleotides. We also show that this variant also has a much slower rate of nucleotide incorporation, which could further disrupt repair capacity in vivo. This study highlights the importance of residues which coordinate the γ-phosphate group of the dNTP when it comes to maintaining nucleotide selectivity, polymerase function, and fidelity. It also emphasizes the importance of further study of this novel human Pol β variant in vivo.