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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & , 2016. "Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10913
    DOI: 10.1038/ncomms10913
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    Cited by:

    1. Bogang Wu & Xiaowen Zhang & Huai-Chin Chiang & Haihui Pan & Bin Yuan & Payal Mitra & Leilei Qi & Hayk Simonyan & Colin N. Young & Eric Yvon & Yanfen Hu & Nu Zhang & Rong Li, 2022. "RNA polymerase II pausing factor NELF in CD8+ T cells promotes antitumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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