Division of Cardiology, Department of Internal Medicine, Dresden University of Technology, Dresden, Germany.
EMBO Rep. 2010 Mar;11(3):208-13. doi: 10.1038/embor.2009.279. Epub 2010 Jan 29.
The cellular response to DNA double-strand break (DSB) occurs through an integrated sensing and signalling network that maintains genomic stability. Oestrogen (E2), among its many functions, is known to have a positive effect on global genomic DNA repair; however, the mechanism by which it functions is unclear. A central enzyme involved in DNA DSB repair in mammalian cells is the DNA-dependent protein kinase (DNA-PK). Here, we show that E2 enhances DNA-PK catalytic subunit (DNA-PKcs) promoter activity with subsequent transcriptional and translational upregulation of DNA-PKcs in a breast cancer cell line. We identify two potential E2 receptor-alpha (ERalpha)-binding sites in a region upstream from the DNA-PKcs initiation site. By using small interfering RNA and the specific E2 receptor antagonist ICI 182,780, we demonstrate that ERalpha knockdown reduces E2-induced upregulation of DNA-PKcs expression and activity in breast carcinoma cells. E2-induced DNA-PK transactivation results in an increased ability of the cells to repair DNA DSB. This previously unknown mechanism of DNA-PK regulation sheds new light on tumour biology and reveals new possibilities for the prevention and therapy of E2-sensitive proliferative diseases.
细胞对 DNA 双链断裂 (DSB) 的反应是通过一个整合的感应和信号网络来实现的，该网络可以维持基因组的稳定性。雌激素 (E2) 在其众多功能中，已知对全球基因组 DNA 修复有积极作用；然而，其作用机制尚不清楚。在哺乳动物细胞中，参与 DNA DSB 修复的一个核心酶是 DNA 依赖性蛋白激酶 (DNA-PK)。在这里，我们发现在乳腺癌细胞系中，E2 增强了 DNA-PK 催化亚基 (DNA-PKcs) 启动子的活性，随后转录和翻译上调了 DNA-PKcs。我们在 DNA-PKcs 起始位点上游的一个区域中鉴定出两个潜在的 E2 受体-α (ERα) 结合位点。通过使用小干扰 RNA 和特异性 E2 受体拮抗剂 ICI 182,780，我们证明 ERα 敲低降低了 E2 诱导的乳腺癌细胞中 DNA-PKcs 表达和活性的上调。E2 诱导的 DNA-PK 转激活导致细胞修复 DNA DSB 的能力增强。这种以前未知的 DNA-PK 调节机制为肿瘤生物学提供了新的见解，并为预防和治疗 E2 敏感的增殖性疾病提供了新的可能性。
