title: Transcriptional activation of DNA-dependent protein kinase catalytic subunit gene expression by oestrogen receptor-alpha.
abstract: 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.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Dresden University of Technology, Dresden, Germany.
authors.forename: Senad
authors.initials: S
authors.lastname: Medunjanin
authors.forename: Sönke
authors.initials: S
authors.lastname: Weinert
authors.forename: David
authors.initials: D
authors.lastname: Poitz
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmeisser
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Strasser
authors.forename: Ruediger C
authors.initials: RC
authors.lastname: Braun-Dullaeus
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D051747:DNA-Activated Protein Kinase / Q000235:genetics* / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D000077267:Fulvestrant; D006801:Humans; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D015533:Transcriptional Activation
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D034741:RNA, Small Interfering; D000077267:Fulvestrant; D004958:Estradiol; D051747:DNA-Activated Protein Kinase