p53 induction, cell cycle checkpoints, and apoptosis in DNAPK- deficient scid mice

The p53 tumor suppressor protein is rapidly induced followingtreatment of cells with agents which cause DNA double strandbreaks (dsbs) leading to cell cycle arrest and/or apoptosis.Scid mutant mice are defective in repair of DNA dsbs which wasrecently shown to be due to lack of DNA-dependent protein kinasc(DNAPK) activity. DNAPK is normally activated by DNA dsbs andphos-phorylates the p53 protein. Here we tested the hypothesisthat DNAPK transduces the signal from DNA dsbs to p53 induction.P53 protein was properly induced in intestinal crypt cells ofirradiated scid mice and was functional as detected by the largeincrease in apoptotic cells. P53 induction was prolonged, consistentwith DNA dsbs as the signal to induce p53. Spontaneous levelsof apoptosis were elevated suggesting that scid mice are sensitiveindicators of spontaneously generated DNA dsbs. Primary scidfibroblasts underwent normal Gl and G2 arrest in response todoxorubicin. DNAPK is not required for p53 induction, cell cyclearrest, or apoptosis after DNA damage.