The DNA damage response (DDR) preserves genomic integrity. Small non-coding RNAs termed DDRNAs are generated at DNA double-strand breaks (DSBs) and are critical for DDR activation. Here we show that active DDRNAs specifically localize to their damaged homologous genomic sites in a transcription-dependent manner. Following DNA damage, RNA polymerase II (RNAPII) binds to the MRE11-RAD50-NBS1 complex, is recruited to DSBs and synthesizes damage-induced long non-coding RNAs (dilncRNAs) from and towards DNA ends. DilncRNAs act both as DDRNA precursors and by recruiting DDRNAs through RNA-RNA pairing. Together, dilncRNAs and DDRNAs fuel DDR focus formation and associate with 53BP1. Accordingly, inhibition of RNAPII prevents DDRNA recruitment, DDR activation and DNA repair. Antisense oligonucleotides matching dilncRNAs and DDRNAs impair site-specific DDR focus formation and DNA repair. We propose that DDR signalling sites, in addition to sharing a common pool of proteins, individually host a unique set of site-specific RNAs necessary for DDR activation.

中文翻译：

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损伤诱导的 lncRNA 通过在单个双链断裂处与 DDRNA 相互作用来控制 DNA 损伤反应。

DNA 损伤反应 (DDR) 保持基因组完整性。称为 DDRNA 的小型非编码 RNA 在 DNA 双链断裂 (DSB) 处产生，对 DDR 激活至关重要。在这里，我们展示了活性 DDRNA 以转录依赖性方式特异性定位到其受损的同源基因组位点。DNA 损伤后，RNA 聚合酶 II (RNAPII) 与 MRE11-RAD50-NBS1 复合物结合，被招募到 DSB 并从 DNA 末端合成损伤诱导的长非编码 RNA (dilncRNA)。DilncRNA 既可作为 DDRNA 前体，也可通过 RNA-RNA 配对招募 DDRNA。dilncRNAs 和 DDRNAs 共同促进 DDR 焦点的形成并与 53BP1 相关联。因此，抑制 RNAPII 可防止 DDRNA 募集、DDR 激活和 DNA 修复。与 dilncRNA 和 DDRNA 匹配的反义寡核苷酸会损害位点特异性 DDR 焦点形成和 DNA 修复。我们建议 DDR 信号位点，除了共享一个共同的蛋白质池外，还单独拥有一组独特的 DDR 激活所必需的位点特异性 RNA。