Abstract
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 β (pol β), a key protein involved in base excision repair, confers a response to cisplatin therapy that is dependent on polymerase activity. Pol β 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 β. Collectively, these results indicate that enhancing pol β activity impedes the efficiency of NER and provide a promising adjuvant therapeutic strategy for cisplatin chemotherapy. IMPLICATIONS: Our studies demonstrate that polβ D160G mutation with enhanced polymerase activity impedes NER efficiency during the repair of cisplatin-induced DNA damage, leading to increased cisplatin sensitivity in cancer cells.
Highlights
Genomic DNA is continuously damaged by environmental and endogenous genotoxic agents
To determine the effect of the D160G mutation on the activity of human pol b, we generated the mutant by site-directed mutagenesis and purified the recombinant protein (Supplementary Fig. S1)
Further experiments were performed to examine whether the modification of pol b polymerase activity by the D160G mutation is due to altered DNA-binding affinity
Summary
Genomic DNA is continuously damaged by environmental and endogenous genotoxic agents. DNA damage can lead to cell death, genomic instability, and mutagenesis. Mammalian cells have evolved complex systems to counteract the harmful effects of DNA damage; these systems are collectively called the DNA damage response. Cancer chemotherapeutic agents such as cis-diamminedichloroplatinum (II; CDDP, best known as cisplatin) exert their cytotoxic effect in cancer cells by inducing excessive DNA damage and activating programmed cell death [2]. In many cases, increased DNA repair capacity in cancer cells leads to drug resistance and severely limits the efficacy of chemotherapeutic drugs [3]. Alterations in DNA repair pathways might prove efficacious when used in combination with DNA-damaging chemotherapeutic drugs [4]
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