Loss of function of the tumor suppressor protein BRCA1 is responsible for a high percentage of familial and also sporadic breast cancers. Early work identified a stimulatory transcriptional coactivator function for the BRCA1 protein, and more recently, BRCA1 has been implicated in transcriptional repression, although few examples of repressed genes have been characterized. We recently used an in vitro transcription assay to identify a biochemical mechanism that explained the BRCA1 stimulatory activity. In this study, we identified an ubiquitin-dependent mechanism by which BRCA1 inhibits transcription. BRCA1 ubiquitinates the transcriptional preinitiation complex, preventing stable association of TFIIE and TFIIH, and thus blocks the initiation of mRNA synthesis. What is striking about this mechanism of regulation by BRCA1 is that the ubiquitination of the preinitiation complex is not targeting proteins for degradation by the proteasome, nor are ubiquitin receptors modifying the activity, but rather the ubiquitin moiety itself interferes with the assembly of basal transcription factors at the promoter. Using RNAi to knockdown expression of the endogenous BRCA1 protein, we assessed the level of repression dependent on BRCA1 in the cell, and we found that BRCA1 is at least as significant a transcriptional repressor as it is an activator. These results define a biochemical mechanism by which the BRCA1 enzymatic activity regulates a key cellular process.

译文

:抑癌蛋白BRCA1的功能丧失导致家族性和散发性乳腺癌的发生率很高。早期的工作确定了BRCA1蛋白具有刺激性的转录共激活因子功能,最近,BRCA1与转录阻抑有关,尽管已鉴定出一些抑制基因的例子。我们最近使用了体外转录测定法来鉴定解释BRCA1刺激活性的生化机制。在这项研究中,我们确定了BRCA1抑制转录的泛素依赖性机制。 BRCA1泛素化转录预启动复合物,阻止TFIIE和TFIIH的稳定缔合,从而阻止mRNA合成的启动。 BRCA1调控机制的惊人之处在于,预启动复合物的泛素化作用既不是针对蛋白酶体降解的蛋白质,也不是泛素受体改变了活性,而是泛素部分本身干扰了基础转录因子的组装。在启动子上。使用RNAi敲低内源性BRCA1蛋白的表达,我们评估了依赖于细胞中BRCA1的抑制水平,我们发现BRCA1至少与激活因子一样重要。这些结果定义了一种生物化学机制,BRCA1酶活性通过该生物化学机制调节关键的细胞过程。

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