Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis

Xiaowen Zhang; Huai Chin Chiang; Yao Wang; Chi Zhang; Sabrina Smith; Xiayan Zhao; Sreejith J. Nair; Joel Michalek; Ismail Jatoi; Meeghan Lautner; Boyce Oliver; Howard Wang; Anna Petit; Teresa Soler; Joan Brunet; Francesca Mateo; Miguel Angel Pujana; Elizabeth Poggi; Krysta Chaldekas; Claudine Isaacs; Beth N. Peshkin; Oscar Ochoa; Frederic Chedin; Constantine Theoharis; Lu Zhe Sun; Tyler J. Curiel; Richard Elledge; Victor X. Jin; Yanfen Hu; Rong Li

doi:10.1038/ncomms15908

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis

Xiaowen Zhang, Huai Chin Chiang, Yao Wang, Chi Zhang, Sabrina Smith, Xiayan Zhao, Sreejith J. Nair, Joel Michalek, Ismail Jatoi, Meeghan Lautner, Boyce Oliver, Howard Wang, Anna Petit, Teresa Soler, Joan Brunet, Francesca Mateo, Miguel Angel Pujana, Elizabeth Poggi, Krysta Chaldekas, Claudine IsaacsBeth N. Peshkin, Oscar Ochoa, Frederic Chedin, Constantine Theoharis, Lu Zhe Sun, Tyler J. Curiel, Richard Elledge, Victor X. Jin, Yanfen Hu, Rong Li

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

125 Scopus citations

Abstract

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5′ end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development.

Original language	English (US)
Article number	15908
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15908
State	Published - Jun 26 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Zhang, X., Chiang, H. C., Wang, Y., Zhang, C., Smith, S., Zhao, X., Nair, S. J., Michalek, J., Jatoi, I., Lautner, M., Oliver, B., Wang, H., Petit, A., Soler, T., Brunet, J., Mateo, F., Angel Pujana, M., Poggi, E., Chaldekas, K., ... Li, R. (2017). Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis. Nature communications, 8, Article 15908. https://doi.org/10.1038/ncomms15908

Zhang, X, Chiang, HC, Wang, Y, Zhang, C, Smith, S, Zhao, X, Nair, SJ, Michalek, J , Jatoi, I, Lautner, M, Oliver, B, Wang, H, Petit, A, Soler, T, Brunet, J, Mateo, F, Angel Pujana, M, Poggi, E, Chaldekas, K, Isaacs, C, Peshkin, BN, Ochoa, O, Chedin, F, Theoharis, C, Sun, LZ, Curiel, TJ, Elledge, R, Jin, VX, Hu, Y & Li, R 2017, 'Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis', Nature communications, vol. 8, 15908. https://doi.org/10.1038/ncomms15908

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title = "Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis",

abstract = "Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5′ end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development.",

author = "Xiaowen Zhang and Chiang, {Huai Chin} and Yao Wang and Chi Zhang and Sabrina Smith and Xiayan Zhao and Nair, {Sreejith J.} and Joel Michalek and Ismail Jatoi and Meeghan Lautner and Boyce Oliver and Howard Wang and Anna Petit and Teresa Soler and Joan Brunet and Francesca Mateo and {Angel Pujana}, Miguel and Elizabeth Poggi and Krysta Chaldekas and Claudine Isaacs and Peshkin, {Beth N.} and Oscar Ochoa and Frederic Chedin and Constantine Theoharis and Sun, {Lu Zhe} and Curiel, {Tyler J.} and Richard Elledge and Jin, {Victor X.} and Yanfen Hu and Rong Li",

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doi = "10.1038/ncomms15908",

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AU - Zhang, Xiaowen

AU - Chiang, Huai Chin

AU - Wang, Yao

AU - Zhang, Chi

AU - Smith, Sabrina

AU - Zhao, Xiayan

AU - Nair, Sreejith J.

AU - Michalek, Joel

AU - Jatoi, Ismail

AU - Lautner, Meeghan

AU - Oliver, Boyce

AU - Wang, Howard

AU - Petit, Anna

AU - Soler, Teresa

AU - Brunet, Joan

AU - Mateo, Francesca

AU - Angel Pujana, Miguel

AU - Poggi, Elizabeth

AU - Chaldekas, Krysta

AU - Isaacs, Claudine

AU - Peshkin, Beth N.

AU - Ochoa, Oscar

AU - Chedin, Frederic

AU - Theoharis, Constantine

AU - Sun, Lu Zhe

AU - Curiel, Tyler J.

AU - Elledge, Richard

AU - Jin, Victor X.

AU - Hu, Yanfen

AU - Li, Rong

PY - 2017/6/26

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N2 - Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5′ end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development.

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Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis

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