Direct stimulation of transcription initiation by BRCA1 requires both its amino and carboxyl termini
Direct stimulation of transcription initiation by BRCA1 requires both its amino and carboxyl termini
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DOI：
10.1074/jbc.c500475200
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发表时间：
2006-03-31
影响因子：
4.8
通讯作者：
Parvin, JD
中科院分区：
文献类型：
--
作者：
Horwitz, AA;Sankaran, S;Parvin, JD
已发表的实验表明，BRCA1与RNAPII的相互作用以及对一些靶基因的调控可能是其作为肿瘤抑制因子的核心作用。以往的体内和体外研究表明，BRCA1的羧基末端参与了转录刺激，但作用机制尚不清楚，而且全长蛋白是否刺激转录也存在争议。BRCA1与许多增强子结合的转录激活子相互作用，表明这些因子将BRCA1招募到启动子，在那里它刺激RNA合成。为了研究BRCA1是否具有内在的转录活性，我们建立了一种完全纯化的转录实验。我们在这里证明了BRCA1通过一系列启动子刺激转录启动。BRCA1的氨基和羧基末端都是这一活性所必需的，但BRCA1结合伙伴BARD1不是必需的。我们的数据支持一个模型，即BRCA1稳定生产性的预起始复合体，从而刺激转录。
Published experiments suggest that BRCA1 interaction with RNAPII and regulation of a number of target genes may be central to its role as a tumor suppressor. Previous in vivo and in vitro work has implicated the carboxyl terminus of BRCA1 in transcriptional stimulation, but the mechanism of action remains unknown, and whether the full- length protein stimulates transcription is controversial. BRCA1 interacts with a number of enhancer- binding transcriptional activators, suggesting that these factors recruit BRCA1 to promoters, where it stimulates RNA synthesis. To investigate whether BRCA1 has intrinsic transcriptional activity, we established a fully purified transcription assay. We demonstrate here that BRCA1 stimulates transcription initiation across a range of promoters. Both the amino and carboxyl termini of BRCA1 are required for this activity, but the BRCA1- binding partner, BARD1, is not. Our data support a model whereby BRCA1 stabilizes productive preinitiation complexes and thus stimulates transcription.