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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Te, 2017. "Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis," Nature Communications, Nature, vol. 8(1), pages 1-12, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15908
    DOI: 10.1038/ncomms15908
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    Cited by:

    1. Eri Koyanagi & Yoko Kakimoto & Tamiko Minamisawa & Fumiya Yoshifuji & Toyoaki Natsume & Atsushi Higashitani & Tomoo Ogi & Antony M. Carr & Masato T. Kanemaki & Yasukazu Daigaku, 2022. "Global landscape of replicative DNA polymerase usage in the human genome," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. 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.
    3. Abhishek Bharadwaj Sharma & Muhammad Khairul Ramlee & Joel Kosmin & Martin R. Higgs & Amy Wolstenholme & George E. Ronson & Dylan Jones & Daniel Ebner & Noor Shamkhi & David Sims & Paul W. G. Wijnhove, 2023. "C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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