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：

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持久性DNA损伤触发整合应激反应的激活，从而在营养限制下促进细胞存活

碱基切除修复（BER）是负责维持基因组完整性的中央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而促进了细胞转化。因此，BER能力的严格适应对于DNA稳定性至关重要。然而，与直觉相反，长时间使细胞暴露于促炎分子或破坏DNA的试剂会通过下调中央支架蛋白XRCC1导致BER缺乏。响应持续性DNA损伤，这种XRCC1下调的基本原理仍然是个谜。基于我们以前的发现，XRCC1的下调会引起广泛的合成代谢变化，我们假设BER耗竭可以提高应激（例如营养限制）下的细胞存活率。这里，我们证明了由XRCC1下调引起的持续单链断裂（SSB）触发了整合应激反应（ISR），以在营养受限的条件下促进细胞存活。ISR激活取决于通过ATM传递的DNA损伤信号，该信号触发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，SSBs可能是由于转录因子Sp1的耗尽而引起的XRCC1水平升高，也可能是由于长时间的氧化应激而在营养限制下触发了ISR介导的细胞存活。最后，ISR途径也可以通过持续的DNA双链断裂来引发。我们的研究结果揭示了持久性DNA损伤之间以前没有发现的联系，