Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis
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.
Zhang, X., Chiang, H., Wang, Y., Zhang, C., Smith, S., Zhao, X., Nair, S., Michalek, J., Jatoi, I., Lautner, M., Oliver, B., Wang, H., Petit, A., Soler, T., Brunet, J., Mateo, F., Angel Pujana, M., Poggi, E., Chaldekas, K., Isaacs, C., Peshkin, B., Ochoa, O., Chedin, F., Theoharis, C., Sun, L., Curiel, T., Elledge, R., Jin, V., Hu, Y., & Li, R. (2017). Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis. Nature Communications, 8 (). http://dx.doi.org/10.1038/ncomms15908