Heterochromatin-Encoded Satellite RNAs Induce Breast Cancer

Mol Cell. 2018 Jun 7;70(5):842-853.e7. doi: 10.1016/j.molcel.2018.04.023. Epub 2018 May 31.


Heterochromatic repetitive satellite RNAs are extensively transcribed in a variety of human cancers, including BRCA1 mutant breast cancer. Aberrant expression of satellite RNAs in cultured cells induces the DNA damage response, activates cell cycle checkpoints, and causes defects in chromosome segregation. However, the mechanism by which satellite RNA expression leads to genomic instability is not well understood. Here we provide evidence that increased levels of satellite RNAs in mammary glands induce tumor formation in mice. Using mass spectrometry, we further show that genomic instability induced by satellite RNAs occurs through interactions with BRCA1-associated protein networks required for the stabilization of DNA replication forks. Additionally, de-stabilized replication forks likely promote the formation of RNA-DNA hybrids in cells expressing satellite RNAs. These studies lay the foundation for developing novel therapeutic strategies that block the effects of non-coding satellite RNAs in cancer cells.

Keywords: BRCA1-associated proteins; DNA damage response; breast tumor formation; heterochromatic RNAs; satellite RNAs.

Publication types

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

MeSH terms

  • Animals
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • DNA Damage*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genomic Instability*
  • HEK293 Cells
  • Heterochromatin / genetics*
  • Heterochromatin / metabolism
  • Humans
  • MCF-7 Cells
  • Mice
  • Protein Binding
  • RNA, Neoplasm / genetics*
  • RNA, Neoplasm / metabolism
  • RNA, Satellite / genetics*
  • RNA, Satellite / metabolism
  • Tumor Burden


  • BRCA1 Protein
  • BRCA1 protein, human
  • Heterochromatin
  • RNA, Neoplasm
  • RNA, Satellite