Transcriptional activation of DNA-dependent protein kinase catalytic subunit gene expression by oestrogen receptor-alpha

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • COS Cells
  • Catalytic Domain
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • DNA-Activated Protein Kinase / genetics*
  • DNA-Activated Protein Kinase / metabolism
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Estrogens / metabolism
  • Fulvestrant
  • Humans
  • Models, Biological
  • RNA, Small Interfering / metabolism
  • Radiation, Ionizing
  • Transcriptional Activation*


  • Estrogen Receptor alpha
  • Estrogens
  • RNA, Small Interfering
  • Fulvestrant
  • Estradiol
  • DNA-Activated Protein Kinase