New role for nuclear hormone receptors and coactivators in regulation of BRCA1-mediated DNA repair in breast cancer cell lines
Year: 2005
Type: article
Abstract: INTRODUCTION: The breast cancer susceptibility gene BRCA1 is involved in the repair of double-strand breaks induced by ionizing radiation and chemotherapy drugs. BRCA1 interacts with coactivators such as p300 and CREB-binding protein (CBP) to activate target gene transcription. Estrogen and retinoic acid receptors (ER and RAR) also require coactivator proteins for their ligand-dependent functions. Few studies have suggested a role for nuclear hormone receptors in DNA repair. METHODS: DNA damage and repair activity were quantified with the use of single-cell gel electrophoresis and plasmid end-joining assays. Cell cycle progression and apoptosis were determined by bromodeoxyuridine and TdT-mediated dUTP nick end labelling assays. Stable transfection was accomplished with the lipofection procedure. Protein interaction and expression were determined by immunoprecipitation and western blotting. RESULTS: 17beta-estradiol (E2) and all-trans retinoic acid (RA) had opposing effects on DNA damage and breast cancer cell survival after double-strand break damage. Treatment with E2, but not with RA, resulted in complex formation between ERalpha, CBP, and BRCA1 in ER-positive cell lines. Mutant BRCA1 reduced the expression and activity of DNA damage repair proteins but did not block nuclear hormone-dependent effects. Mutant BRCA1 failed to form complexes with ERalpha and CBP, which correlated with its ability to exert E2-independent effects on DNA repair. Mutant BRCA1 inhibited cell cycle progression and produced increased survival in cells with double-strand breaks. Ectopic ERalpha expression reproduced the E2-mediated effects on DNA damage, repair, and survival. CONCLUSION: The present study proposes a new mechanism by which ER and RAR regulate BRCA1-mediated DNA repair by means of CBP.
Source: Breast Cancer Research
DOI: 10.1186/bcr1362
Authors: David L Crowe, Matt K Lee
Institution: University of Southern California
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
OpenAlex ID: W1764653742