Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells
Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells
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DOI：
10.1128/mcb.24.19.8504-8518.2004
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发表时间：
2004-10-01
影响因子：
5.3
通讯作者：
Glazer, PM
中科院分区：
文献类型：
--
作者：
Bindra, RS;Schaffer, PJ;Glazer, PM
有一个新兴的概念认为，癌细胞中的获得性遗传不稳定可能是由于细胞应激，如炎症和缺氧，导致关键的DNA修复途径失调所致。在这里，我们报告低氧特异性地下调RAD51的表达，RAD51是哺乳动物细胞中同源重组的关键介质。在低氧暴露期间，在多种类型的癌细胞中观察到RAD51水平的降低，并且与细胞周期曲线或低氧诱导因子的表达无关。对RAD51基因启动子活性以及mRNA和蛋白质稳定性的分析表明，低氧对该基因的调控是通过转录抑制来实现的。在复氧后的48h，RAD51的低表达也在缺氧后的细胞中持续存在。相应地，我们发现低氧和低氧后细胞的同源重组水平降低，这表明低氧相关的RAD51表达的减少对DNA修复具有功能性后果。此外，通过对小鼠实验性肿瘤的免疫荧光图像分析，在体内证实了低氧介导的RAD51下调。基于这些发现，我们提出了一种新的机制，即肿瘤微环境中的遗传不稳定是由低氧诱导的癌细胞同源重组途径抑制所介导的。RAD51表达的异常调节也可能造成肿瘤内细胞间DNA损伤反应的异质性，这可能与癌症治疗的反应有关。
There is an emerging concept that acquired genetic instability in cancer cells can arise from the dysregulation of critical DNA repair pathways due to cell stresses such as inflammation and hypoxia. Here we report that hypoxia specifically down-regulates the expression of RAD51, a key mediator of homologous recombination in mammalian cells. Decreased levels of Rad51 were observed in multiple cancer cell types during hypoxic exposure and were not associated with the cell cycle profile or with expression of hypoxia-inducible factor. Analyses of RAD51 gene promoter activity, as well as mRNA and protein stability, indicate that the hypoxia-mediated regulation of this gene occurs via transcriptional repression. Decreased expression of Rad51 was also observed to persist in posthypoxic cells for as long as 48 h following reoxygenation. Correspondingly, we found reduced levels of homologous recombination in both hypoxic and posthypoxic cells, suggesting that the hypoxia-associated reduction in Rad51 expression has functional consequences for DNA repair. In addition, hypoxia-mediated down-regulation of Rad51 was confirmed in vivo via immunofluorescent image analysis of experimental tumors in mice. Based on these findings, we propose a novel mechanism of genetic instability in the tumor microenvironment mediated by hypoxia-induced suppression of the homologous recombination pathway in cancer cells. The aberrant regulation of Rad51 expression may also create heterogeneity in the DNA damage response among cells within tumors, with implications for the response to cancer therapies.