Heterochromatin-Encoded Satellite RNAs Induce Breast Cancer.

Abstract

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.

• Authors: Quan Zhu, Nien Hoong, Aaron Aslanian, Toshiro Hara, Christopher Benner, Sven Heinz, Karen H Miga, Eugene Ke, Sachin Verma, Jan Soroczynski, John R Yates 3rd, Tony Hunter, Inder M Verma
• Journal: Molecular cell (Mol Cell) Vol. 70 Issue 5 Pg. 842-853.e7 (06 07 2018) ISSN: 1097-4164 [Electronic] United States
• PMID: 29861157 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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