Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development
Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development
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DOI：
10.1038/ncomms10913
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发表时间：
2016-03-01
影响因子：
16.6
通讯作者：
Li, Rong
中科院分区：
文献类型：
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作者：
Nair, Sreejith J.;Zhang, Xiaowen;Li, Rong
乳腺癌易感基因BRCA1因其在双链断裂(DSB)DNA修复中的作用而广为人知。虽然BRCA1也与转录调控有关，但其生理意义尚不清楚。COBRA1(也称为NELF-B)是一种BRCA1结合蛋白，调节RNA聚合酶II(RNAPII)的暂停和转录延伸。在这里，我们询问了BRCA1和COBRA1在小鼠乳腺发育过程中的功能相互作用。组织特异性缺失的COBRA1基因减少了乳腺上皮细胞的隔膜，阻碍了导管的形态发生、肺泡发生和乳汁发生，显示了COBRA1在成人组织发育中的关键作用。值得注意的是，由于Cobra1基因敲除而导致的这些发育缺陷在很大程度上可以通过额外的全长BRCA1的丢失来挽救。此外，BRCA1/Cobra1双敲除恢复了青春期的发育转录，改变了腔上皮的动态平衡，但仍然缺乏基于同源重组的DSB修复。因此，我们的基因抑制分析揭示了BRCA1在乳腺发育过程中对抗COBRA1依赖的转录程序的一种先前未被认识的、DNA修复独立的功能。
The breast cancer susceptibility gene BRCA1 is well known for its function in double-strand break (DSB) DNA repair. While BRCA1 is also implicated in transcriptional regulation, the physiological significance remains unclear. COBRA1 (also known as NELF-B) is a BRCA1-binding protein that regulates RNA polymerase II (RNAPII) pausing and transcription elongation. Here we interrogate functional interaction between BRCA1 and COBRA1 during mouse mammary gland development. Tissue-specific deletion of Cobra1 reduces mammary epithelial compartments and blocks ductal morphogenesis, alveologenesis and lactogenesis, demonstrating a pivotal role of COBRA1 in adult tissue development. Remarkably, these developmental deficiencies due to Cobra1 knockout are largely rescued by additional loss of full-length Brca1. Furthermore, Brca1/Cobra1 double knockout restores developmental transcription at puberty, alters luminal epithelial homoeostasis, yet remains deficient in homologous recombination-based DSB repair. Thus our genetic suppression analysis uncovers a previously unappreciated, DNA repair-independent function of BRCA1 in antagonizing COBRA1-dependent transcription programme during mammary gland development.