Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids

Shira Sagie, Shir Toubiana, Stella R. Hartono, Hagar Katzir, Aya Tzur-Gilat, Shany Havazelet, Claire Francastel, Guillaume Velasco, Frédéric Chédin and Sara Selig ()
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Shira Sagie: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion
Shir Toubiana: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion
Stella R. Hartono: University of California
Hagar Katzir: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion
Aya Tzur-Gilat: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion
Shany Havazelet: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion
Claire Francastel: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, CNRS UMR7216
Guillaume Velasco: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, CNRS UMR7216
Frédéric Chédin: University of California
Sara Selig: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract DNA:RNA hybrids, nucleic acid structures with diverse physiological functions, can disrupt genome integrity when dysregulated. Human telomeres were shown to form hybrids with the lncRNA TERRA, yet the formation and distribution of these hybrids among telomeres, their regulation and their cellular effects remain elusive. Here we predict and confirm in several human cell types that DNA:RNA hybrids form at many subtelomeric and telomeric regions. We demonstrate that ICF syndrome cells, which exhibit short telomeres and elevated TERRA levels, are enriched for hybrids at telomeric regions throughout the cell cycle. Telomeric hybrids are associated with high levels of DNA damage at chromosome ends in ICF cells, which are significantly reduced with overexpression of RNase H1. Our findings suggest that abnormally high TERRA levels in ICF syndrome lead to accumulation of telomeric hybrids that, in turn, can result in telomeric dysfunction.

Date: 2017
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DOI: 10.1038/ncomms14015

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