Deciphering phenotypic variance in different models of DNA-PKcs deficiency.

•DNA-PKcs deficiency has been studied exhaustively. In cell culture models, ablation of DNA-PK's catalytic activity results in a cell phenotype that is virtually indistinguishable from that ascribed to complete loss of the enzyme.•But, the same kinase inactivating mutation in living mice results in a markedly more severe phenotype.•Here, we investigate potential explanations for these and other controversial results in studies of this important enzyme.