Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids.
Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids.
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DOI：
10.1038/ncomms14015
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发表时间：
2017-01-24
影响因子：
16.6
通讯作者：
Selig S
中科院分区：
文献类型：
--
作者：
Sagie S;Toubiana S;Hartono SR;Katzir H;Tzur-Gilat A;Havazelet S;Francastel C;Velasco G;Chédin F;Selig S
DNA:RNA杂交，具有多种生理功能的核酸结构，当失调时可以破坏基因组的完整性。人类端粒被证明与lncRNA TERRA形成杂交，然而这些杂交在端粒之间的形成和分布、它们的调控和它们的细胞效应仍然是难以捉摸的。在这里，我们预测并确认在几种人类细胞类型，DNA:RNA杂交形成在许多亚端粒和端粒区域。我们证明，在整个细胞周期中，端粒短且TERRA水平升高的ICF综合征细胞在端粒区域富集。在ICF细胞中，端粒杂交与染色体末端的高水平DNA损伤有关，这种损伤随着RNase H1的过度表达而显著减少。我们的研究结果表明，在ICF综合征中，异常高的TERRA水平会导致端粒杂交的积累，进而导致端粒功能障碍。ICF综合征细胞表现出端粒缩短和非编码RNA TERRA水平升高。在这里，作者表明这与高水平的DNA损伤有关，表明由于DNA: RNA杂交的形成，端粒功能障碍增加
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. ICF syndrome cells exhibit shortened telomeres and elevated levels of the noncoding RNA TERRA. Here the authors show this is associated with high levels of DNA damage, suggesting an increase in telomere dysfunction due to the formation of DNA: RNA hybrids