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; Rong Li

doi:10.1038/ncomms10913

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, Rong Li

Molecular Medicine

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English (US)
Article number	10913
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10913
State	Published - Mar 4 2016

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Nair, S. J., Zhang, X., Chiang, H. C., Jahid, M. J., Wang, Y., Garza, P., April, C., Salathia, N., Banerjee, T., Alenazi, F. S., Ruan, J., Fan, J. B., Parvin, J. D., Jin, V. X., Hu, Y., & Li, R. (2016). Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development. Nature communications, 7, [10913]. https://doi.org/10.1038/ncomms10913

Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development. / Nair, Sreejith J.; Zhang, Xiaowen; Chiang, Huai Chin; Jahid, Md Jamiul; Wang, Yao; Garza, Paula; April, Craig; Salathia, Neeraj; Banerjee, Tapahsama; Alenazi, Fahad S.; Ruan, Jianhua; Fan, Jian Bing; Parvin, Jeffrey D.; Jin, Victor X.; Hu, Yanfen; Li, Rong.

In: Nature communications, Vol. 7, 10913, 04.03.2016.

Research output: Contribution to journal › Article › peer-review

Nair, Sreejith J. ; Zhang, Xiaowen ; Chiang, Huai Chin ; Jahid, Md Jamiul ; Wang, Yao ; Garza, Paula ; April, Craig ; Salathia, Neeraj ; Banerjee, Tapahsama ; Alenazi, Fahad S. ; Ruan, Jianhua ; Fan, Jian Bing ; Parvin, Jeffrey D. ; Jin, Victor X. ; Hu, Yanfen ; Li, Rong. / Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development. In: Nature communications. 2016 ; Vol. 7.

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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).",

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T1 - Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development

AU - Nair, Sreejith J.

AU - Zhang, Xiaowen

AU - Chiang, Huai Chin

AU - Jahid, Md Jamiul

AU - Wang, Yao

AU - Garza, Paula

AU - April, Craig

AU - Salathia, Neeraj

AU - Banerjee, Tapahsama

AU - Alenazi, Fahad S.

AU - Ruan, Jianhua

AU - Fan, Jian Bing

AU - Parvin, Jeffrey D.

AU - Jin, Victor X.

AU - Hu, Yanfen

AU - Li, Rong

N1 - 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).

PY - 2016/3/4

Y1 - 2016/3/4

N2 - 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.

AB - 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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