Sustaining DNA damage response (DDR) signalling via retention of DDR factors at damaged sites is important for transmitting damage-sensing and repair signals. Herein, we found that DNA damage provoked the association of ribosomes with IRES region in lncRNA CTBP1-DT, which overcame the negative effect of upstream open reading frames (uORFs), and elicited the novel microprotein DNA damage-upregulated protein (DDUP) translation via a cap-independent translation mechanism. Activated ATR kinase-mediated phosphorylation of DDUP induced a drastic ‘dense-to-loose’ conformational change, which sustained the RAD18/RAD51C and RAD18/PCNA complex at damaged sites and initiated RAD51C-mediated homologous recombination and PCNA-mediated post-replication repair mechanisms. Importantly, treatment with ATR inhibitor abolished the effect of DDUP on chromatin retention of RAD51C and PCNA, thereby leading to hypersensitivity of cancer cells to DNA-damaging chemotherapeutics. Taken together, our results uncover a plausible mechanism underlying the DDR sustaining and might represent an attractive therapeutic strategy in improvement of DNA damage-based anticancer therapies.

中文翻译：

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LncRNA CTBP1-DT 编码的微生物蛋白 DDUP 维持 DNA 损伤反应信号以触发双重 DNA 修复机制

通过在受损部位保留 DDR 因子来维持 DNA 损伤反应 (DDR) 信号传导对于传输损伤感应和修复信号非常重要。在此，我们发现 DNA 损伤引发了核糖体与 lncRNA CTBP1-DT 中 IRES 区域的结合，克服了上游开放阅读框 (uORF) 的负面影响，并通过一种与上限无关的翻译机制。激活的 ATR 激酶介导的 DDUP 磷酸化诱导剧烈的“从密集到松散”的构象变化，这在受损位点维持 RAD18/RAD51C 和 RAD18/PCNA 复合物，并启动 RAD51C 介导的同源重组和 PCNA 介导的复制后修复机制。重要的，用 ATR 抑制剂治疗消除了 DDUP 对 RAD51C 和 PCNA 染色质保留的影响，从而导致癌细胞对破坏 DNA 的化疗药物过敏。总之，我们的研究结果揭示了 DDR 维持的一个合理机制，并可能代表一种有吸引力的治疗策略，以改善基于 DNA 损伤的抗癌疗法。