Transcriptional autoregulation by BRCA1.
Transcriptional autoregulation by BRCA1.
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DOI：
10.1158/0008-5472.can-09-1477
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发表时间：
2010-01-15
期刊：
影响因子：
11.2
通讯作者：
Gardner K
中科院分区：
文献类型：
--
作者：
De Siervi A;De Luca P;Byun JS;Di LJ;Fufa T;Haggerty CM;Vazquez E;Moiola C;Longo DL;Gardner K
BRCA1基因产物在调节基因组完整性方面发挥着多种作用。它参与各种超分子复合体的组装以应对DNA损伤的能力已经得到了广泛的研究，但对于BRCA1的S作为基因特异性转录辅助调节因子的直接作用却知之甚少。BRCA1缺失或突变与遗传性乳腺癌和卵巢癌密切相关，大量报道表明BRCA1表达水平的改变常见于散发性乳腺癌，提示BRCA1转录调控在肿瘤发生中也可能起重要作用。在这份报告中，我们提供了BRCA1的S作为转录协同调节因子与通过自动调节转录环路控制其表达之间惊人联系的证据。BRCA1与含有E2F-1和RB的复合体组装形成抑制BRCA1启动子转录的多组分转录复合体。这种复合体被基因毒性胁迫破坏，导致BRCA1启动子上的BRCA1蛋白被置换，随后BRCA1转录上调。体内BRCA1缺失的细胞显示BRCA1转录上调，而过度表达BRCA1的细胞BRCA1转录下调。串联染色质免疫沉淀研究表明，BRCA1是由BRCA1启动子上含有BRCA1、E2F1和RB的动态共调节复合体调控的，该复合体被DNA损伤剂破坏以增加其转录。这些发现定义了一种新的转录机制，其中BRCA1的表达受自动调节的稳态控制，该稳态选择性地滴定BRCA1的水平，以保持基因组的完整性，以响应遗传毒性的侮辱。
The BRCA1 gene product plays numerous roles in regulating genome integrity. Its ability to participate in the assembly of various super-molecular complexes in response to DNA damage has been extensively studied, however much less is understood about BRCA1’s direct role as a gene-specific transcriptional co-regulator. BRCA1 loss or mutation is highly associated with hereditary breast and ovarian cancer and numerous reports show that altered levels of BRCA1 expression are frequently found in sporadic forms of breast cancer, suggesting that control of BRCA1 transcription may also play a significant role in tumorigenesis. In this report we provide evidence of a stunning linkage between BRCA1’s role as a transcriptional co-regulator and the control of its expression via an auto-regulatory transcriptional loop. BRCA1 assembles with complexes containing E2F-1 and RB to form a repressive multi-component transcriptional complex that inhibits BRCA1 promoter transcription. This complex is disrupted by genotoxic stress resulting in the displacement of BRCA1 protein from the BRCA1 promoter and subsequent up-regulation of BRCA1 transcription. Cells depleted of BRCA1 in vivo show up-regulation of BRCA1 transcripts while cells over-expressing BRCA1 show BRCA1 transcript down-regulation. Tandem chromatin immmuno-precipitation studies demonstate that BRCA1 is regulated by a dynamic co-regulatory complex containing BRCA1, E2F1 and Rb at the BRCA1 promoter that is disrupted by DNA damaging agents to increase its transcription. These findings define a novel transcriptional mechanism in which BRCA1 expression is controlled by an autoregulated homeostasis that selectively titrates its levels to maintain genome integrity in response to genotoxic insult.