Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development

Sreejith J. Nair, Xiaowen Zhang, Huai-Chin Chiang, Md Jamiul Jahid, Yao Wang, Paula Garza, Craig April, Neeraj Salathia, Tapahsama Banerjee, Fahad S. Alenazi, Jianhua Ruan, Jian-Bing Fan, Jeffrey D. Parvin, Victor X. Jin, Yanfen Hu () and Rong Li ()
Additional contact information
Sreejith J. Nair: The University of Texas Health Science Center at San Antonio
Xiaowen Zhang: The University of Texas Health Science Center at San Antonio
Huai-Chin Chiang: The University of Texas Health Science Center at San Antonio
Md Jamiul Jahid: The University of Texas at San Antonio
Yao Wang: The University of Texas Health Science Center at San Antonio
Paula Garza: The University of Texas Health Science Center at San Antonio
Craig April: Research and Development, Illumina, Inc.
Neeraj Salathia: Research and Development, Illumina, Inc.
Tapahsama Banerjee: The Ohio State University
Fahad S. Alenazi: The University of Texas at San Antonio
Jianhua Ruan: The University of Texas at San Antonio
Jian-Bing Fan: Research and Development, Illumina, Inc.
Jeffrey D. Parvin: The Ohio State University
Victor X. Jin: The University of Texas Health Science Center at San Antonio
Yanfen Hu: The University of Texas Health Science Center at San Antonio
Rong Li: The University of Texas Health Science Center at San Antonio

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10913

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