IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.
Nat Commun. 2017 Feb 27;8:13980. doi: 10.1038/ncomms13980.
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.
DNA 损伤反应 (DDR) 是一组细胞事件，发生在 DNA 损伤产生之后。最近，已证实特定位置的小型非编码 RNA，也称为 DNA 损伤反应 RNA (DDRNAs)，在 DDR 信号转导和 DNA 修复中发挥作用。功能失调的端粒在衰老、癌症和越来越多已确定的病理条件中激活 DDR。在这里，我们表明在哺乳动物中，端粒功能障碍会诱导端粒 DDRNAs (tDDRNAs) 及其来自两条 DNA 链的更长前体的转录。端粒处的 DDR 激活和维持依赖于 tDDRNAs 的生物发生和功能。通过序列特异性反义寡核苷酸对其功能进行抑制，使得在培养细胞和小鼠组织中的端粒特异性 DDR 失活成为可能，这在以前是无法实现的。总之，这些结果表明 tDDRNAs 在功能失调的端粒处被诱导，并且对于 DDR 的激活是必需的，它们通过靶向 DDRNAs 验证了针对特定基因座的 DDR 抑制的可行性。
