BRD7, a subunit of SWI/SNF complexes, binds directly to BRCA1 and regulates BRCA1-dependent transcription.
We carried out a yeast two-hybrid screen using a BRCA1 bait composed of amino acids 1 to 1142 and identified BRD7 as a novel binding partner of BRCA1. This interaction was confirmed by coimmunoprecipitation of endogenous BRCA1 and BRD7 in T47D and HEK-293 cells. BRD7 is a bromodomain containing protein, which is a subunit of PBAF-specific Swi/Snf chromatin remodeling complexes. To determine the functional consequences of the BRCA1-BRD7 interaction, we investigated the role of BRD7 in BRCA1-dependent transcription using microarray-based expression profiling. We found that a variety of targets were coordinately regulated by BRCA1 and BRD7, such as estrogen receptor alpha (ERalpha). Depletion of BRD7 or BRCA1 in either T47D or MCF7 cells resulted in loss of expression of ERalpha at both the mRNA and protein level, and this loss of ERalpha was reflected in resistance to the antiestrogen drug fulvestrant. We show that BRD7 is present, along with BRCA1 and Oct-1, on the ESR1 promoter (the gene which encodes ERalpha). Depletion of BRD7 prevented the recruitment of BRCA1 and Oct-1 to the ESR1 promoter; however, it had no effect on the recruitment of the other Swi/Snf subunits BRG1, BAF155, and BAF57 or on RNA polymerase II recruitment. These results support a model whereby the regulation of ERalpha transcription by BRD7 is mediated by its recruitment of BRCA1 and Oct-1 to the ESR1 promoter.
Harte
Mary T
MT
Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, Northern Ireland, United Kingdom. m.harte@qub.ac.uk
O'Brien
Garrett J
GJ
Ryan
Niamh M
NM
Gorski
Julia J
JJ
Savage
Kienan I
KI
Crawford
Nyree T
NT
Mullan
Paul B
PB
Harkin
D Paul
DP
D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D006801:Humans; D047468:Immunoprecipitation; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D000092468:Bromodomain Containing Proteins
D019313:BRCA1 Protein; D002868:Chromosomal Proteins, Non-Histone; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D050811:Octamer Transcription Factor-1; D034741:RNA, Small Interfering; C492913:BRCA1 protein, human; C485694:BRD7 protein, human; D000092468:Bromodomain Containing Proteins; C494165:POU2F1 protein, human