Enhanced Activity of Variant DNA Polymerase β (D160G) Contributes to Cisplatin Therapy by Impeding the Efficiency of NER

Cisplatin, commonly used in a variety of cancer treatments, induces apoptosis in cancer cells by causing lethal DNA damage. Several DNA repair pathways participate in regulation of cisplatin treatment, leading to cisplatin sensitivity or resistance in cancer cells. DNA polymerase beta (pol beta), a key protein involved in base excision repair, confers a response to cisplatin therapy that is dependent on polymerase activity. Pol beta D160G mutation with enhanced polymerase activity, previously identified in clear cell renal cell carcinoma, enhances the sensitivity of human cancer cells and mouse xenografts to cisplatin by limiting the efficiency of nucleotide excision repair (NER). Notably, the D160G mutation impedes the recruitment of XPA to cisplatin-induced sites of DNA damage, leading to unrepaired damage and further inducing cell death. Molecular architecture analysis indicated that the D160G mutation alters protein-DNA interactions and the surface electrostatic properties of the DNA-binding regions, resulting in greater DNA affinity and polymerase activity compared with wild-type pol beta. Collectively, these results indicate that enhancing pol beta activity impedes the efficiency of NER and provide a promising adjuvant therapeutic strategy for cisplatin chemotherapy.