BARD1 regulates BRCA1-mediated transactivation of the p21WAF1/CIP1 and Gadd45 promoters.
BRCA1 regulates gene transcription as part of its tumor suppressor function. Prior studies on BRCA1 transactivation did not account for the impact of its binding partner, BARD1. Here we tested the effect of BARD1 on BRCA1 transactivation of the p21 and Gadd45 promoters. We show that BARD1 promoted nuclear accumulation of BRCA1, but repressed BRCA1-mediated transactivation by up to 75% in transfected cells normalized for nuclear BRCA1 levels. The BRCA1 (C61G) RING mutant transactivation function was not regulated by BARD1. We propose that BARD1 reduces BRCA1 transcriptional activity, and that this at least partly involves BRCA1/BARD1 E3 ubiquitin ligase activity, which is disrupted by the C61G mutation.
Fabbro
Megan
M
Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute at Westmead Hospital, Darcy Road, P.O. Box 412, Westmead, NSW 2145, Australia.
Henderson
Beric R
BR
D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000494:pharmacology*; D000097642:GADD45 Proteins
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; C493956:CDKN1A protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C102449:BARD1 protein, human