Pericentromeric satellite repeat expansions through RNA-derived DNA intermediates in cancer.

Abstract

Aberrant transcription of the pericentromeric human satellite II (HSATII) repeat is present in a wide variety of epithelial cancers. In deriving experimental systems to study its deregulation, we observed that HSATII expression is induced in colon cancer cells cultured as xenografts or under nonadherent conditions in vitro, but it is rapidly lost in standard 2D cultures. Unexpectedly, physiological induction of endogenous HSATII RNA, as well as introduction of synthetic HSATII transcripts, generated cDNA intermediates in the form of DNA/RNA hybrids. Single molecule sequencing of tumor xenografts showed that HSATII RNA-derived DNA (rdDNA) molecules are stably incorporated within pericentromeric loci. Suppression of RT activity using small molecule inhibitors reduced HSATII copy gain. Analysis of whole-genome sequencing data revealed that HSATII copy number gain is a common feature in primary human colon tumors and is associated with a lower overall survival. Together, our observations suggest that cancer-associated derepression of specific repetitive sequences can promote their RNA-driven genomic expansion, with potential implications on pericentromeric architecture.

• Authors: Francesca Bersani, Eunjung Lee, Peter V Kharchenko, Andrew W Xu, Mingzhu Liu, Kristina Xega, Olivia C MacKenzie, Brian W Brannigan, Ben S Wittner, Hyunchul Jung, Sridhar Ramaswamy, Peter J Park, Shyamala Maheswaran, David T Ting, Daniel A Haber
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 49 Pg. 15148-53 (Dec 08 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26575630 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• DNA, Satellite
• RNA

Topics

• Centromere (genetics)
• Colorectal Neoplasms (genetics, pathology)
• DNA, Satellite (genetics)
• Humans
• Neoplasms (genetics)
• Nucleic Acid Hybridization
• RNA (genetics)
• Repetitive Sequences, Nucleic Acid