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

  • Author(s): Zhang, Xiaowen
  • Chiang, Huai-Chin
  • Wang, Yao
  • Zhang, Chi
  • Smith, Sabrina
  • Zhao, Xiayan
  • Nair, Sreejith J
  • Michalek, Joel
  • Jatoi, Ismail
  • Lautner, Meeghan
  • Oliver, Boyce
  • Wang, Howard
  • Petit, Anna
  • Soler, Teresa
  • Brunet, Joan
  • Mateo, Francesca
  • Angel Pujana, Miguel
  • Poggi, Elizabeth
  • Chaldekas, Krysta
  • Isaacs, Claudine
  • Peshkin, Beth N
  • Ochoa, Oscar
  • Chedin, Frederic
  • Theoharis, Constantine
  • Sun, Lu-Zhe
  • Curiel, Tyler J
  • Elledge, Richard
  • Jin, Victor X
  • Hu, Yanfen
  • Li, Rong
  • et al.
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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