BRD7, a Subunit of SWI/SNF Complexes, Binds Directly to BRCA1 and Regulates BRCA1-Dependent Transcription
BRD7, a Subunit of SWI/SNF Complexes, Binds Directly to BRCA1 and Regulates BRCA1-Dependent Transcription
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DOI：
10.1158/0008-5472.can-09-2089
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发表时间：
2010-03-15
期刊：
影响因子：
11.2
通讯作者：
Harkin, D. Paul
中科院分区：
文献类型：
--
作者：
Harte, Mary T.;O'Brien, Garrett J.;Harkin, D. Paul
我们使用由氨基酸1 ~ 1142组成的BRCA1诱饵进行酵母双杂交筛选，发现BRD7是BRCA1的一个新的结合伙伴。T47D和HEK-293细胞中内源性BRCA1和BRD7的共免疫沉淀证实了这种相互作用。BRD7是一种含溴结构域的蛋白，是pbaf特异性Swi/Snf染色质重塑复合物的一个亚基。为了确定BRCA1-BRD7相互作用的功能后果，我们使用基于微阵列的表达谱研究了BRD7在brca1依赖性转录中的作用。我们发现BRCA1和BRD7协调调节多种靶点，如雌激素受体a （ER α）。在T47D或MCF7细胞中，BRD7或BRCA1的缺失导致ERa在mRNA和蛋白水平上的表达缺失，这种ERa的缺失反映在对抗雌激素药物氟维司汀的抗性上。我们发现BRD7与BRCA1和Oct-1一起存在于ESR1启动子（编码ER α的基因）上。BRD7的缺失阻止了BRCA1和Oct-1向ESR1启动子的募集；然而，它对其他Swi/Snf亚基BRG1、BAF155和BAF57的募集或RNA聚合酶II的募集没有影响。这些结果支持了一个模型，即BRD7对ER α转录的调节是通过BRCA1和Oct-1募集到ESR1启动子介导的。癌症Res;70 (6);2538 - 47。AACR (C) 2010。
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 a (ER alpha). Depletion of BRD7 or BRCA1 in either T47D or MCF7 cells resulted in loss of expression of ERa at both the mRNA and protein level, and this loss of ERa 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 ER alpha). 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 ER alpha transcription by BRD7 is mediated by its recruitment of BRCA1 and Oct-1 to the ESR1 promoter. Cancer Res; 70(6); 2538-47. (C)2010 AACR.