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BRCA1 function in transcription

机译：BRCA1在转录中的功能

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The breast and ovarian specific tumor suppressor protein, BRCA1, is associated with the transcriptional regulatory machine termed the RNA polymerase II (Pol II) holoenzyme. Experiments support a model in which molecules such as the BRCA1 protein and the CREB binding protein (CBP) function similarly as regulatory targets which link the enhancer-binding regulatory proteins to the basal transcriptional machinery. As an example, phosphorylated CREB protein interacts with the CBP molecule present in the holoenzyme complex and will activate transcription in vitro. We propose a similar model for the BRCA1 protein, but with a different subset of upstream activators functioning via BRCA1 to regulate the Pol II holoenzyme. We have established an in vitro transcriptional assay dependent upon the carboxy-terminal domain of BRCA1 fused to the DNA-binding domain of GAL4. We have also shown that both CBP and BRCA1 are linked to the Pol II holoenzyme complex via a common subunit -- the RNA Helicase A (RHA) protein.CBP binds to an amino terminal domain of RHA, and BRCA1 binds to a separate internal domain of RHA, and truncated RHA molecules have been shown to be dominant negative transcriptional repressors of either CBP or BRCA1. Since most tumor-associated BRCA1 mutations result in the truncation of the BRCA1 protein and loss of its carboxy-terminal holoenzyme interaction domain, it is suggested that an important component of the tumor suppressive function of BRCA1 occurs via the gene expression process.
机译：乳腺癌和卵巢特异性肿瘤抑制蛋白BRCA1与称为RNA聚合酶II（Pol II）全酶的转录调控机器有关。实验支持一种模型，其中诸如BRCA1蛋白和CREB结合蛋白（CBP）的分子的功能类似于调控靶标，后者将与增强子结合的调控蛋白连接到基础转录机制。例如，磷酸化的CREB蛋白与全酶复合物中存在的CBP分子相互作用，并在体外激活转录。我们为BRCA1蛋白提出了一个相似的模型，但是上游激活子的不同子集通过BRCA1来调节Pol II全酶。我们已经建立了一种体外转录测定方法，该方法取决于与GAL4的DNA结合结构域融合的BRCA1的羧基末端结构域。我们还显示CBP和BRCA1都通过一个共同的亚基-RNA Helicase A（RHA）蛋白与Pol II全酶复合体相连.CBP结合到RHA的氨基末端结构域，而BRCA1结合到单独的内部结构域RHA和截短的RHA分子已被证明是CBP或BRCA1的显性负转录阻遏物。由于大多数与肿瘤相关的BRCA1突变会导致BRCA1蛋白的截断和其羧基末端全酶相互作用域的丢失，因此建议通过基因表达过程发生BRCA1抑癌功能的重要组成部分。

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