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 () and Rong Li ()
Additional contact information
Xiaowen Zhang: University of Texas Health Science Center at San Antonio
Huai-Chin Chiang: University of Texas Health Science Center at San Antonio
Yao Wang: University of Texas Health Science Center at San Antonio
Chi Zhang: University of Texas Health Science Center at San Antonio
Sabrina Smith: University of Texas Health Science Center at San Antonio
Xiayan Zhao: University of Texas Health Science Center at San Antonio
Sreejith J. Nair: University of Texas Health Science Center at San Antonio
Joel Michalek: University of Texas Health Science Center at San Antonio
Ismail Jatoi: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio
Meeghan Lautner: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio
Boyce Oliver: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio
Howard Wang: Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio
Anna Petit: University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
Teresa Soler: University Hospital of Bellvitge, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
Joan Brunet: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Girona Biomedical Research Institute (IDIBGI)
Francesca Mateo: Breast Cancer and Systems Biology Lab, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
Miguel Angel Pujana: Breast Cancer and Systems Biology Lab, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
Elizabeth Poggi: Lombardi Comprehensive Cancer Center, Georgetown University
Krysta Chaldekas: Lombardi Comprehensive Cancer Center, Georgetown University
Claudine Isaacs: Lombardi Comprehensive Cancer Center, Georgetown University
Beth N. Peshkin: Lombardi Comprehensive Cancer Center, Georgetown University
Oscar Ochoa: PRMA Plastic Surgery
Frederic Chedin: University of California
Constantine Theoharis: South Texas Pathology Associates
Lu-Zhe Sun: University of Texas Health Science Center at San Antonio
Tyler J. Curiel: University of Texas Health Science Center at San Antonio
Richard Elledge: University of Texas Health Science Center at San Antonio
Victor X. Jin: University of Texas Health Science Center at San Antonio
Yanfen Hu: University of Texas Health Science Center at San Antonio
Rong Li: University of Texas Health Science Center at San Antonio

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15908

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