Strikingly, most Aldh2−/−Fancd2−/− HSCs failed to engraft (Fig. 4b). It is possible that HSCs that carry heavy DNA-damage burdens are eliminated, and selection pressure favours the survival of less damaged stem cells. It was therefore important to determine the mechanism of HSC loss in Aldh2−/−Fancd2−/− mice, and if attenuated, it would be important to determine the mutagenic consequences. p53 protein regulates the cellular response to DNA damage and, when activated, induces restorative processes or apoptosis. We found that Aldh2−/−Fancd2−/− haematopoietic stem and progenitor cells (HSPCs) accumulated p53 and cleaved caspase-3, indicating that endogenous-aldehyde stress activates the p53 response (Extended Data Fig. 6a–c). Furthermore, we found that genetic ablation of p53 partially suppressed the acetaldehyde hypersensitivity of Fancd2-deficient splenic B cells and granulocyte/macrophage colony forming units (Extended Data Fig. 6d, e).
