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首页> 外文期刊>Biochemical Pharmacology >Expression and regulation of RAD51 mediate cellular responses to chemotherapeutics
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Expression and regulation of RAD51 mediate cellular responses to chemotherapeutics

机译：RAD51的表达和调控介导细胞对化学疗法的反应

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There is evidence that RAD51 expression associates with resistance to commonly used chemotherapeutics. Our previous work demonstrated that inhibitors of thymidylate synthase (TS) induced RAD51-dependent homologous recombination (HR), and depleting the RAD51 recombinase sensitized cells to TS inhibitors. In this study, the consequences of RAD51 over-expression were studied. Over-expression of wild-type RAD51 (～6-fold above endogenous RAD51) conferred resistance to TS inhibitors. In contrast, over-expression of a mutant RAD51 (T309A) that is incapable of being phosphorylated rendered cells more chemosensitive. Moreover, over-expression of the T309A mutant acted in a dominant negative manner over endogenous RAD51 by causing the reduced localization of RAD51 foci following treatment with TS inhibitors. To measure the effect of mutant RAD51 on the cellular response to other DNA damaging chemotherapeutics, the topoisomerase poison etoposide was utilized. Cells over-expressing wild-type RAD51 showed reduced DNA strand breaks, while cells over-expressing the mutant RAD51 showed more than twice as many strand breaks, suggesting that the mutant RAD51 was actively inhibiting strand break resolution. To directly demonstrate an effect on HR, wild-type RAD51 and T309A mutant RAD51 were transiently expressed in HeLa cells that contained an HR reporter construct. HR events provoked by DNA breaks induced by the I-SceI endonuclease increased in cells expressing wild-type RAD51 and decreased in cells expressing the T309A mutant. Collectively, the data suggest that interference with the activation of RAD51-mediated HR represents a potentially useful anticancer target for combination therapies.
机译：有证据表明，RAD51的表达与对常用化学疗法的抗性有关。我们以前的工作表明，胸苷酸合酶（TS）抑制剂可诱导RAD51依赖的同源重组（HR），并使RAD51重组酶致敏细胞向TS抑制剂耗竭。在这项研究中，研究了RAD51过表达的后果。野生型RAD51的过度表达（比内源RAD51高约6倍）赋予了对TS抑制剂的抗性。相反，过表达不能被磷酸化的RAD51（T309A）突变体使细胞更加化学敏感。此外，T309A突变体的过表达通过引起TS抑制剂处理后引起RAD51病灶的定位减少，而以超过内源RAD51的显性负作用。为了测量突变RAD51对细胞对其他DNA破坏性化学疗法的反应的影响，使用了拓扑异构酶毒依托泊苷。过表达野生型RAD51的细胞显示出减少的DNA链断裂，而过表达突变型RAD51的细胞显示出两倍以上的链断裂，这表明突变型RAD51正在积极抑制链断裂的分解。为了直接证明对HR的作用，野生型RAD51和T309A突变体RAD51在含有HR报告基因构建体的HeLa细胞中瞬时表达。由I-SceI核酸内切酶诱导的DNA断裂引起的HR事件在表达野生型RAD51的细胞中增加，而在表达T309A突变体的细胞中减少。总体而言，数据表明，对RAD51介导的HR激活的干扰代表了联合治疗的潜在有用抗癌靶标。

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