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

Nat Commun. 2017 Jun 26;8:15908. doi: 10.1038/ncomms15908.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / chemistry*
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • Breast / enzymology
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinogenesis
  • Female
  • Humans
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nucleic Acid Conformation
  • Promoter Regions, Genetic
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism*
  • RNA-Binding Proteins
  • Tumor Suppressor Proteins / chemistry*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Brca1 protein, mouse
  • Cobra1 protein, mouse
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Tumor Suppressor Proteins
  • RNA Polymerase II