HSCs mutated by aldehydes are functionally compromised and display myeloid bias. The p53 response is critical in driving the loss in number and function of HSCs. Although Trp53 deletion rescues HSC defects, this, paradoxically, does not result in further genomic instability at the single HSC level. It is important to emphasize, however, that the pool of HSCs is larger, and therefore there is still an overall increase in mutation. Nevertheless, our work implies that the relationship between p53, DNA repair and genome stability is more complex in stem cells than previously appreciated. The central role for ALDH2 in removing genotoxic aldehydes has implications for the more than 540 million people who are deficient in ALDH2 activity. Alcohol exposure in such individuals may cause DNA double-strand breaks and chromosome rearrangements3. This large population may also be susceptible to alcohol-induced age-related blood disorders. More generally, this research provides a simple plausible explanation for the established epidemiological link between alcohol consumption and enhanced cancer risk4,29.
