Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10913
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Funding
- National Institutes of Health (NIH) [CA170306]
- NIH [G12MD007591, P20CA165589, CA141090, CA161349, CA184084]
- Tom C. & H. Frost Endowment
- Max and Minnie Tomerlin Voelcker Fund
- Avon Foundation for Women
- Department of Defense Predoctoral Fellowship [W81XWH-09-1-0014]
- Cancer Therapy and Research Center at University of Texas Health Science Center at San Antonio [P30CA054174]
- Div Of Information & Intelligent Systems
- Direct For Computer & Info Scie & Enginr [1218201] Funding Source: National Science Foundation
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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.
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