Hydrogen Peroxide induces resistance to DNA damage in a localization and p53 dependent manner

Organisms need to be able to adapt to a changing environment in order to survive. The adaptive response invoked by a low dose of a stressor resulting in resistance to high levels of that stressor is known as hormesis and can even lead to lifespan extension of organisms. The exact mechanisms underlying stress-induced hormesis are unknown, although multiple studies pose mitochondria-derived Reactive Oxygen Species (ROS, e.g. H ₂ O ₂ ) as an important contributor. Here we used chemo-genetic H ₂ O ₂ production as a model to study ROS-dependent adaptive responses in a localization-dependent manner. We found that brief, sublethal H ₂ O ₂ production at the nucleosomes provides p53-dependent resistance to a subsequent high dose of H ₂ O ₂ , whereas mitochondrial H ₂ O ₂ production, surprisingly, does not. A multi-omics approach revealed that p53-induced hormesis is accompanied by metabolic rewiring that boosts reductive capacity, and that the increased stress resistance can mostly be attributed to its downstream target p21. Importantly, brief p53 stabilization also mounted protection against chemotherapy-induced DNA damage, suggesting that p53-dependent hormesis could be exploited to selectively protect healthy, p53-wildtype tissue from chemotherapy in the treatment of patients with p53 mutant tumors.