期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15908
关键词
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资金
- National Institutes of Health [NIH CA170306]
- NIH [ES022057, GM114142, CA164122, CA161349]
- Skinner Endowment
- Holly Beach Public Library
- Alamo Breast Cancer Foundation
- Congressionally Directed Medical Research Program [WSlXWH-14-1-0129]
- Tom C. & H. Frost Endowment
- NCI [T32CA148724]
- Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio [P30CA054174]
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 50 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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