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.
Highlights
Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors
We found that R-loop intensity in BRCA1 mutation carriers (B1, n 1⁄4 55) was significantly higher than that in non-carriers (NC, n 1⁄4 36, Po0.001 by two-tailed t-test, Fig. 1a,b)
Combined studies of clinical samples, cell culture and genetically engineered mouse models lead us to the conclusion that negative elongation factor (NELF)-mediated polymerase II (Pol II) pausing is an important source of R-loop accumulation in BRCA1-deficient mammary epithelial cells
Summary
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 It is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. BRCA1 is best known for its roles in supporting homologous recombination (HR)-based double-strand break repair[7,8,9] and suppressing DNA replication stress[10,11,12,13,14,15] It is not known whether loss of these functions, which are ubiquitously important to all proliferating cells, is sufficient to account for cell lineage-specific tumorigenesis in breast epithelium of women carrying BRCA1 mutations. We found that BRCA1 mutation-associated R-loops preferentially accumulate in luminal epithelial cells and at genomic loci with paused Pol II. Our work uncovers a previously unappreciated functional antagonism between BRCA1 and Pol II pausing in breast tumorigenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
