title: Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids.
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.
authors.affiliation: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Shira
authors.identifier: 0000-0001-7234-0256
authors.initials: S
authors.lastname: Sagie
authors.affiliation: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Shir
authors.initials: S
authors.lastname: Toubiana
authors.affiliation: Department of Molecular and Cellular Biology and Genome Center, University of California, Davis, California 95616, USA.
authors.forename: Stella R
authors.initials: SR
authors.lastname: Hartono
authors.affiliation: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Hagar
authors.initials: H
authors.lastname: Katzir
authors.affiliation: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Aya
authors.initials: A
authors.lastname: Tzur-Gilat
authors.affiliation: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Shany
authors.initials: S
authors.lastname: Havazelet
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, CNRS UMR7216, Paris Cedex 75205, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Francastel
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, CNRS UMR7216, Paris Cedex 75205, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Velasco
authors.affiliation: Department of Molecular and Cellular Biology and Genome Center, University of California, Davis, California 95616, USA.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chédin
authors.affiliation: Molecular Medicine Laboratory, Rambam Health Care Campus and Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Selig
mesh_terms: D002460:Cell Line; D043171:Chromosomal Instability / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D005145:Face / Q000002:abnormalities*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000097:blood / Q000235:genetics*; D008214:Lymphocytes; D061251:Primary Cell Culture; D000081207:Primary Immunodeficiency Diseases; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D016914:Ribonuclease H / Q000378:metabolism; D016615:Telomere / Q000235:genetics*; D059506:Telomere Shortening / Q000235:genetics
chemical_list: D062085:RNA, Long Noncoding; D004247:DNA; D016914:Ribonuclease H; C078856:ribonuclease HI