Base-excision repair (BER) is a central DNA repair mechanism responsible for the maintenance of genome integrity. Accordingly, BER defects have been implicated in cancer, presumably by precipitating cellular transformation through an increase in the occurrence of mutations. Hence, tight adaptation of BER capacity is essential for DNA stability. However, counterintuitive to this, prolonged exposure of cells to pro-inflammatory molecules or DNA-damaging agents causes a BER deficiency by downregulating the central scaffold protein XRCC1. The rationale for this XRCC1 downregulation in response to persistent DNA damage remains enigmatic. Based on our previous findings that XRCC1 downregulation causes wide-ranging anabolic changes, we hypothesised that BER depletion could enhance cellular survival under stress, such as nutrient restriction. Here, we demonstrate that persistent single-strand breaks (SSBs) caused by XRCC1 downregulation trigger the integrated stress response (ISR) to promote cellular survival under nutrient-restricted conditions. ISR activation depends on DNA damage signalling via ATM, which triggers PERK-mediated eIF2α phosphorylation, increasing translation of the stress-response factor ATF4. Furthermore, we demonstrate that SSBs, induced either through depletion of the transcription factor Sp1, responsible for XRCC1 levels, or through prolonged oxidative stress, trigger ISR-mediated cell survival under nutrient restriction as well. Finally, the ISR pathway can also be initiated by persistent DNA double-strand breaks. Our results uncover a previously unappreciated connection between persistent DNA damage, caused by a decrease in BER capacity or direct induction of DNA damage, and the ISR pathway that supports cell survival in response to genotoxic stress with implications for tumour biology and beyond.

中文翻译：

---

持续的 DNA 损伤触发整合应激反应的激活，以促进细胞在营养限制下的生存


碱基切除修复 (BER) 是负责维持基因组完整性的核心 DNA 修复机制。因此，BER 缺陷可能与癌症有关，可能是通过增加突变的发生来促进细胞转化。因此，BER 容量的严格调整对于 DNA 稳定性至关重要。然而，与直觉相反的是，细胞长时间暴露于促炎分子或 DNA 损伤剂，会下调中心支架蛋白 XRCC1，从而导致 BER 缺陷。 XRCC1 因持续 DNA 损伤而下调的原理仍然是个谜。根据我们之前的发现，XRCC1 下调会导致广泛的合成代谢变化，我们假设 BER 消耗可以增强细胞在压力（例如营养限制）下的存活率。在这里，我们证明 XRCC1 下调引起的持续单链断裂 (SSB) 会触发综合应激反应 (ISR)，从而促进营养限制条件下的细胞存活。 ISR 激活取决于通过 ATM 发出的 DNA 损伤信号，ATM 会触发 PERK 介导的 eIF2α 磷酸化，从而增加应激反应因子 ATF4 的翻译。此外，我们证明，通过消耗负责 XRCC1 水平的转录因子 Sp1 或通过长期氧化应激诱导的 SSB，也会在营养限制下触发 ISR 介导的细胞存活。最后，ISR 途径也可以通过持续的 DNA 双链断裂来启动。 我们的研究结果揭示了由 BER 能力下降或直接诱导 DNA 损伤引起的持续性 DNA 损伤与支持细胞存活以应对基因毒性应激的 ISR 通路之间的联系，这对肿瘤生物学及其他领域具有重要意义。