The p53 response to DNA damage in vivo is independent of DNA-dependent protein kinase

Ionizing radiation (IR) exposure causes mammalian cells to undergo p53-depe ndent cell cycle arrest and/or apoptosis. The in vivo role of DNA-dependent protein kinase (DNA-PK) in the transduction of the DNA damage signal to p5 3 remains unresolved. To determine the relationship between DNA-PK and p53, we studied the cell cycle and apoptotic responses to IR in mice deficient in DNA-PK. Using the slip mouse, which harbors an inactivating mutation of the DNA-PK catalytic subunit (DNA-PKcs), we demonstrated not only that thes e DNA-PKcs null mutants were highly radiosensitive but also that upon IR tr eatment, p53 accumulated in their cultured cells and tissue. Induced p53 wa s transcriptionally active and mediated the induction of p21 and Bar in sli p cells. Examination of the thymic cell cycle response to IR treatment indi cated that the slip G(1)/S-phase cell cycle checkpoint function was intact. We further show that slip mice exhibited a higher level of spontaneous thy mic apoptosis as well as a more robust apoptotic response to IR than wild-t ype mice. Together, these data demonstrate that the p53-mediated response t o DNA damage is intact in cells devoid of DNA-PK activity and suggest that other kinases, such as the product of the gene (ATM) mutated in ataxia tela ngiectasia, are better candidates for regulating IR-induced phosphorylation and accumulation of p53.