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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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