Nuclear DNA damage contributes to cellular malfunction and the premature onset of age-related diseases, including cancer. Until recently, the canonical DNA damage response (DDR) was thought to represent a collection of nuclear processes that detect, signal and repair damaged DNA. However, recent evidence suggests that beyond nuclear events, the DDR rewires an intricate network of metabolic circuits, fine-tunes protein synthesis, trafficking, and secretion as well as balances growth with defense strategies in response to genotoxic insults. In this review, we discuss how the active DDR signaling mobilizes extranuclear and systemic responses to promote cellular homeostasis and organismal survival in health and disease.

核DNA损伤会导致细胞功能异常以及与年龄有关的疾病（包括癌症）的过早发作。直到最近，人们仍认为规范的DNA损伤反应（DDR）代表检测，信号传递和修复受损DNA的核过程的集合。但是，最近的证据表明，除了核事件以外，DDR还重新构建了复杂的代谢回路网络，对蛋白质合成，运输和分泌进行了微调，并在应对遗传毒性侮辱时平衡了防御策略的增长。在这篇综述中，我们讨论了主动DDR信号转导如何调动核外和全身反应，以促进健康和疾病中的细胞稳态和机体存活。