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:
- Negin Khosraviani & V. Talya Yerlici & Jonathan St-Germain & Yi Yang Hou & Shi Bo Cao & Carla Ghali & Michael Bokros & Rehna Krishnan & Razqallah Hakem & Stephen Lee & Brian Raught & Karim Mekhail, 2024.
"Nucleolar Pol II interactome reveals TBPL1, PAF1, and Pol I at intergenic rDNA drive rRNA biogenesis,"
Nature Communications, Nature, vol. 15(1), pages 1-17, December.
- 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.
- 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.
- 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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