Title

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

Authors

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, University of Texas Health Science Center at San Antonio
Meeghan Lautner, University of Texas Health Science Center at San Antonio
Boyce Oliver, University of Texas Health Science Center at San Antonio
Howard Wang, University of Texas Health Science Center at San Antonio
Anna Petit, Hospital Universitari de Bellvitge
Teresa Soler, Hospital Universitari de Bellvitge
Joan Brunet, Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta
Francesca Mateo, Hospital Universitari de Bellvitge
Miguel Angel Pujana, Hospital Universitari de Bellvitge
Elizabeth Poggi, Georgetown Lombardi Comprehensive Cancer Center
Krysta Chaldekas, Georgetown Lombardi Comprehensive Cancer Center
Claudine Isaacs, Georgetown Lombardi Comprehensive Cancer Center
Beth N. Peshkin, Georgetown Lombardi Comprehensive Cancer Center
Oscar Ochoa, PRMA Plastic Surgery
Frederic Chedin, University of California, Davis
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

Document Type

Journal Article

Publication Date

6-26-2017

Journal

Nature Communications

Volume

8

DOI

10.1038/ncomms15908

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.

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