文章：

无嘌呤/无嘧啶核酸酶在多发性骨髓瘤同源重组调控中的作用：机制与转化意义

Role of apurinic/apyrimidinic nucleases in the regulation of homologous recombination in myeloma: mechanisms and translational significance

原文发布日期：2018-09-25

DOI: 10.1038/s41408-018-0129-9

类型: Article

开放获取: 是

英文摘要：

We have previously reported that homologous recombination (HR) is dysregulated in multiple myeloma (MM) and contributes to genomic instability and development of drug resistance. We now demonstrate that base excision repair (BER) associated apurinic/apyrimidinic (AP) nucleases (APEX1 and APEX2) contribute to regulation of HR in MM cells. Transgenic as well as chemical inhibition of APEX1 and/or APEX2 inhibits HR activity in MM cells, whereas the overexpression of either nuclease in normal human cells, increases HR activity. Regulation of HR by AP nucleases could be attributed, at least in part, to their ability to regulate recombinase (RAD51) expression. We also show that both nucleases interact with major HR regulators and that APEX1 is involved in P73-mediated regulation of RAD51 expression in MM cells. Consistent with the role in HR, we also show that AP-knockdown or treatment with inhibitor of AP nuclease activity increases sensitivity of MM cells to melphalan and PARP inhibitor. Importantly, although inhibition of AP nuclease activity increases cytotoxicity, it reduces genomic instability caused by melphalan. In summary, we show that APEX1 and APEX2, major BER proteins, also contribute to regulation of HR in MM. These data provide basis for potential use of AP nuclease inhibitors in combination with chemotherapeutics such as melphalan for synergistic cytotoxicity in MM.

摘要翻译： 

我们此前曾报道，同源重组（HR）在多发性骨髓瘤（MM）中调控异常，并导致基因组不稳定性和耐药性的产生。目前我们证实，碱基切除修复（BER）相关的脱嘌呤/脱嘧啶（AP）核酸内切酶（APEX1和APEX2）参与调控MM细胞中的HR。转基因及化学抑制APEX1和/或APEX2可抑制MM细胞中的HR活性，而在正常人类细胞中过表达这两种核酸内切酶中的任一种，则会增强HR活性。AP核酸内切酶对HR的调控可能至少部分归因于其调控重组酶（RAD51）表达的能力。我们还发现，这两种核酸内切酶与主要的HR调控因子相互作用，且APEX1参与P73介导的MM细胞中RAD51表达的调控。与HR中的作用一致，我们还发现AP敲低或AP核酸内切酶活性抑制剂处理可增加MM细胞对美法仑和PARP抑制剂的敏感性。重要的是，虽然抑制AP核酸内切酶活性会增加细胞毒性，但它能减少由美法仑引起的基因组不稳定性。总之，我们证实主要的BER蛋白APEX1和APEX2也参与调控MM中的HR。这些数据为AP核酸内切酶抑制剂与美法仑等化疗药物联合用于MM协同细胞毒作用的潜在应用提供了依据。

原文链接：

Role of apurinic/apyrimidinic nucleases in the regulation of homologous recombination in myeloma: mechanisms and translational significance