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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‐α (ERα)‐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 ERα 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.

Transcriptional activation of DNA‐dependent protein kinase catalytic subunit gene expression by oestrogen receptor‐α