BER is a highly coordinated process in which the scaffold protein XRCC1 occupies a critical role due to its ability to stabilise the two other core BER components DNA polymerase β and DNA ligase III. Base-excision repair (BER) is a centrally important DNA repair mechanism responsible for correcting many of these small base lesions and single-strand breaks. This leads to a high level of DNA lesions even under physiological ‘unstressed’ circumstances that are in constant need of repair to avert potential mutagenic and cytotoxic consequences. However, even in the absence of exogenous noxious influences, DNA is prone to spontaneous alterations, due to its chemical reactivity in the aquatic milieu and reactive side-products that are created by the cellular metabolism. Sources of DNA damage include a wide variety of exogenous damaging agents. 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.ĭNA damage is considered the molecular origin of many pathophysiological processes such as ageing, neurodevelopmental and neurodegenerative disorders, and cancer. Finally, the ISR pathway can also be initiated by persistent DNA double-strand breaks. 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. ISR activation depends on DNA damage signalling via ATM, which triggers PERK-mediated eIF2α phosphorylation, increasing translation of the stress-response factor ATF4. 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. 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. The rationale for this XRCC1 downregulation in response to persistent DNA damage remains enigmatic. 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. Hence, tight adaptation of BER capacity is essential for DNA stability. Accordingly, BER defects have been implicated in cancer, presumably by precipitating cellular transformation through an increase in the occurrence of mutations. Base-excision repair (BER) is a central DNA repair mechanism responsible for the maintenance of genome integrity.
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