Ionizing radiation and interstrand DNA crosslinking compounds provide impor
tant treatments against cancer due to their extreme genotoxicity for prolif
erating cells. Both the efficacies of such treatments and the mutagenic pot
ential of these agents are modulated by the ability of cells to repair the
inflicted DNA damage. Here we demonstrate that homologous recombination-def
icient mRAD54(-/-) mice are hypersensitive to ionizing radiation at the emb
ryonic but, unexpectedly, not at the adult stage. However, at the adult sta
ge mRAD54 deficiency dramatically aggravates the ionizing radiation sensiti
vity of severe combined immune deficiency (scid) mice that are impaired in
DNA double-strand break repair through DNA end-joining. In contrast, regard
less of developmental stage, mRAD54-/- mice are hypersensitive to the inter
strand DNA crosslinking compound mitomycin C, These results demonstrate tha
t the two major DNA double-strand break repair pathways in mammals have ove
rlapping as well as specialized roles, and that the relative contribution o
f these pathways towards repair of ionizing radiation-induced DNA damage ch
anges during development of the animal.