To do this, we crossed mice deficient in the known Fanconi anaemia repair gene Fanca with mice lacking the key NHEJ factor Ku70. We failed to obtain Fanca−/−Ku70−/− mice, indicating that there was a synthetic lethal interaction between Ku70-dependent NHEJ and Fanconi anaemia-crosslink repair (Supplementary Information Table 1). To bypass embryonic lethality, we generated blood-specific Fanca knockout mice (Extended Data Fig. 3) and crossed them with Ku70+/− mice to produce mice that had the double mutation in the blood compartment (Fancafl/-Ku70−/− Vav1-iCre). These mice were viable, indicating that the embryonic lethality of Fanca−/−Ku70−/− is not due to failed blood production (Supplementary Information Table 1). However, blood counts show that Fancafl/-Ku70−/− Vav1-iCre mice are anaemic (Fig. 3a) and have fewer HSCs compared to congenic controls (Fig. 3b–e). Fancafl/-Ku70−/− Vav1-iCre mice also display genomic instability, with increased frequency of micronuclei-containing NCEs (Fig. 3f). Finally, we tested whether Ku70 was required to maintain resistance of short-term (ST) HSCs to aldehydes by exposing bone marrow cells to acetaldehyde in vitro before injecting them into lethally irradiated recipients. Fancafl/-Ku70−/− Vav1-iCre ST-HSCs were much more sensitive
