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.
Highlights
DNA:RNA hybrids, nucleic acid structures with diverse physiological functions, can disrupt genome integrity when dysregulated
The data presented here demonstrate for the first time that DNA:RNA hybrids form at chromosome ends in primary WT fibroblasts and in lymphoblastoid cells (LCLs) lines derived from normal individuals
Using the whole-genome DNA:RNA hybrid immunoprecipitation (DRIP)-seq approach, these hybrids are detected in the majority, but not in all, of chromosome ends in human fibroblasts and in the NT2 human embryonal carcinoma cell line (Fig. 1b,c)
Summary
DNA:RNA hybrids, nucleic acid structures with diverse physiological functions, can disrupt genome integrity when dysregulated. We predict and confirm in several human cell types that DNA:RNA hybrids form at many subtelomeric and telomeric regions. Various studies indicate that DNA:RNA hybrids have a positive effect on gene transcription and are beneficial to the cell[22,23,24,25], these structures have been shown to mediate genome instability and replication stress[26]. Our findings establish that telomeric DNA:RNA hybrids occur in primary human cells and that subtelomeric sequences have an effect on generation of telomeric hybrids. We demonstrate that elevated TERRA levels are associated with higher levels of telomeric hybrids in ICF syndrome and suggest a role for these DNA:RNA hybrids in promoting damage and instability at telomeric regions in this disease
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