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

Abstract

The p53 tumor suppressor protein is rapidly induced following treatment of cells with agents which cause DNA double strand breaks (dsbs) leading to cell cycle arrest and/or apoptosis. Scid mutant mice are defective in repair of DNA dsbs which was recently shown to be due to lack of DNA-dependent protein kinasc (DNAPK) activity. DNAPK is normally activated by DNA dsbs and phos-phorylates the p53 protein. Here we tested the hypothesis that DNAPK transduces the signal from DNA dsbs to p53 induction. P53 protein was properly induced in intestinal crypt cells of irradiated scid mice and was functional as detected by the large increase in apoptotic cells. P53 induction was prolonged, consistent with DNA dsbs as the signal to induce p53. Spontaneous levels of apoptosis were elevated suggesting that scid mice are sensitive indicators of spontaneously generated DNA dsbs. Primary scid fibroblasts underwent normal Gl and G2 arrest in response to doxorubicin. DNAPK is not required for p53 induction, cell cycle arrest, or apoptosis after DNA damage.