Upon genotoxic stresses, cells employ various DNA damage responses (DDRs), including DNA damage repair or apoptosis, to safeguard genome integrity. However, the determinants among different DDRs choices are largely unknown. Here, we report angiopoietin-like protein 8 (ANGPTL8), a secreted regulator of lipid metabolism, localizes to the nucleus and acts as a dynamic switch that directs DDRs towards apoptosis rather than DNA repair after genotoxin exposure. ANGPTL8 deficiency alleviates DNA damage and apoptosis in cells exposed to genotoxins, as well as in the liver or kidney of mice injured by hepatic ischemia/reperfusion or cisplatin treatment. Mechanistically, ANGPTL8 physically interacts with Poly (ADP-ribose) polymerase 1 (PARP1), in a PARylation-independent manner, and reduces the fluidity of PARP1-DNA condensates, thereby enhancing the pro-apoptotic accumulation of PARP1 and PAR chains on DNA lesions. However, the transcription of ANGPTL8 is gradually decreased following genotoxin treatment, partly due to downregulation of CCAAT enhancer binding protein alpha (CEBPA), presumably to avoid further cytotoxicity. Together, we provide new insights by which genotoxic stress induced DDRs are channeled to suicidal apoptosis to safeguard genome integrity.

在基因毒性应激下，细胞利用各种 DNA 损伤反应 （DDR），包括 DNA 损伤修复或细胞凋亡，以保护基因组完整性。然而，不同 DDR 选择之间的决定因素在很大程度上是未知的。在这里，我们报道了血管生成素样蛋白 8 （ANGPTL8） 是脂质代谢的分泌调节剂，定位于细胞核并充当动态开关，在基因毒素暴露后引导 DDRs 走向细胞凋亡而不是 DNA 修复。ANGPTL8缺陷减轻了暴露于基因毒素的细胞以及因肝缺血/再灌注或顺铂治疗而受伤的小鼠肝脏或肾脏的 DNA 损伤和凋亡。从机制上讲，ANGPTL8 以不依赖 PARylation 的方式与 Poly （ADP-ribose） 聚合酶 1 （PARP1） 物理相互作用，并降低 PARP1-DNA 缩合物的流动性，从而增强 PARP1 和 PAR 链在 DNA 损伤上的促凋亡积累。然而，基因毒素处理后 ANGPTL8 的转录逐渐减少，部分原因是 CCAAT 增强子结合蛋白 α （CEBPA） 的下调，可能是为了避免进一步的细胞毒性。我们共同提供了新的见解，通过这些见解，遗传毒性应激诱导的 DDRs 被引导至自杀性细胞凋亡以保护基因组完整性。