Enhanced Activity of Variant DNA Polymerase β (D160G) Contributes to Cisplatin Therapy by Impeding the Efficiency of NER
Enhanced Activity of Variant DNA Polymerase β (D160G) Contributes to Cisplatin Therapy by Impeding the Efficiency of NER
复制标题
变体 DNA 聚合酶 beta (D160G) 的活性增强通过阻碍 NER 的效率来促进顺铂治疗
DOI：
10.1158/1541-7786.mcr-19-0482
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发表时间：
2019-10-01
影响因子：
5.2
通讯作者：
Guo，Zhigang
中科院分区：
文献类型：
--
作者：
Wang，Meina;Li，Enjie;Guo，Zhigang
顺铂，通常用于各种癌症治疗，通过引起致命的DNA损伤诱导癌细胞凋亡。几种DNA修复途径参与顺铂治疗的调节，导致癌细胞对顺铂敏感或耐药。DNA聚合酶β（pol β）是参与碱基切除修复的关键蛋白，其对顺铂治疗的反应依赖于聚合酶活性。先前在肾透明细胞癌中发现的聚合酶活性增强的Pol β D160 G突变通过限制核苷酸切除修复（NER）的效率来增强人癌细胞和小鼠异种移植物对顺铂的敏感性。值得注意的是，D160 G突变阻碍XPA募集到顺铂诱导的DNA损伤位点，导致未修复的损伤并进一步诱导细胞死亡。分子结构分析表明D160 G突变改变了蛋白质-DNA相互作用和DNA结合区域的表面静电性质，导致与野生型pol β相比更大的DNA亲和力和聚合酶活性。这些结果表明，polβ D160 G突变和polβ D160 G活性增强可抑制NER的效率，从而提高肿瘤细胞对顺铂的敏感性。
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.ImplicationsOur 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.