@article{8a4aabd25a114cbb9cc6c7e4bf17c2ea,
title = "Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development",
abstract = "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.",
author = "Nair, {Sreejith J.} and Xiaowen Zhang and Chiang, {Huai Chin} and Jahid, {Md Jamiul} and Yao Wang and Paula Garza and Craig April and Neeraj Salathia and Tapahsama Banerjee and Alenazi, {Fahad S.} and Jianhua Ruan and Fan, {Jian Bing} and Parvin, {Jeffrey D.} and Jin, {Victor X.} and Yanfen Hu and Rong Li",
note = "Funding Information: We thank Drs Anthony Wynshaw-Boris for the MMTV-Cre mouse strain, Jonathan Gelfond for assistance in statistical analysis, and Tyler Curiel for critical reading of the manuscript. The work was supported by grants to Y.H. from the National Institutes of Health (NIH CA170306), to J.R. from NIH (G12MD007591, P20CA165589), to J.D.P. from NIH (CA141090), and to R.L. from NIH (CA161349 and CA184084), the Tom C. & H. Frost Endowment, the Max and Minnie Tomerlin Voelcker Fund, and Avon Foundation for Women. S.J.N was supported by a Department of Defense Predoctoral Fellowship (W81XWH-09-1-0014). We also thank generous support from Cancer Therapy and Research Center at University of Texas Health Science Center at San Antonio (P30CA054174). Funding Information: We thank Drs Anthony Wynshaw-Boris for the MMTV-Cre mouse strain, Jonathan Gelfond for assistance in statistical analysis, and Tyler Curiel for critical reading of the manuscript. The work was supported by grants to Y.H. from the National Institutes of Health (NIH CA170306), to J.R. from NIH (G12MD007591, P20CA165589), to J.D.P. from NIH (CA141090), and to R.L. from NIH (CA161349 and CA184084), the Tom C. & H. Frost Endowment, the Max and Minnie Tomerlin Voelcker Fund, and Avon Foundation for Women. S.J.N was supported by a Department of Defense Predoctoral Fellowship (W81XWH-09-1-0014). We also thank generous support from Cancer Therapy and Research Center at University of Texas Health Science Center at San Antonio (P30CA054174).",
year = "2016",
month = mar,
day = "4",
doi = "10.1038/ncomms10913",
language = "English (US)",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}