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首页> 外文期刊>Nature Communications >DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs
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DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs

机译：通过调节端粒DNA损伤反应RNA抑制功能失调的端粒的DNA损伤反应

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摘要

The DNA damage response (DDR) is a set of cellular events that follows the generation of DNA damage. Recently, site-specific small non-coding RNAs, also termed DNA damage response RNAs (DDRNAs), have been shown to play a role in DDR signalling and DNA repair. Dysfunctional telomeres activate DDR in ageing, cancer and an increasing number of identified pathological conditions. Here we show that, in mammals, telomere dysfunction induces the transcription of telomeric DDRNAs (tDDRNAs) and their longer precursors from both DNA strands. DDR activation and maintenance at telomeres depend on the biogenesis and functions of tDDRNAs. Their functional inhibition by sequence-specific antisense oligonucleotides allows the unprecedented telomere-specific DDR inactivation in cultured cells and in vivo in mouse tissues. In summary, these results demonstrate that tDDRNAs are induced at dysfunctional telomeres and are necessary for DDR activation and they validate the viability of locus-specific DDR inhibition by targeting DDRNAs.
机译：DNA损伤反应（DDR）是继DNA损伤产生后的一系列细胞事件。最近，已显示出位点特异性的小型非编码RNA，也称为DNA损伤反应RNA（DDRNA），在DDR信号传导和DNA修复中发挥作用。功能失调的端粒在衰老，癌症和越来越多的已确定病理状况中激活DDR。在这里，我们表明，在哺乳动物中，端粒功能障碍诱导了两条DNA链的端粒DDRNA（tDDRNA）及其更长的前体的转录。端粒的DDR激活和维持取决于tDDRNA的生物发生和功能。序列特异性反义寡核苷酸对它们的功能抑制使培养细胞和小鼠组织体内的端粒特异性DDR灭活前所未有。总之，这些结果表明，tDDRNAs在功能失调的端粒处被诱导，并且是DDR激活所必需的，并且它们通过靶向DDRNAs来验证基因座特异性DDR抑制的可行性。

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