RADIOSENSITIVITY IN ATAXIA-TELANGIECTASIA FIBROBLASTS IS NOT ASSOCIATED WITH DEREGULATED APOPTOSIS

Ataxia telangiectasia (AT) is an autosomal recessive human disorder fe aturing diverse clinical abnormalities including proneness to cancer a nd extreme sensitivity to ionizing radiation. Although cells from AT p atients exhibit faulty activation of the p53 signal transduction pathw ay at early times after radiation exposure, it has been proposed that high levels of DNA damage persisting in AT cells may up-regulate p53 t hrough an ATM-independent mechanism at late times after irradiation, l eading to cell death by apoptosis. In this study we demonstrate that d iploid skin fibroblast strains homozygous for the AT mutation fail to up-regulate p53 protein at late times (less than or equal to 48 h) aft er irradiation with Co-60 gamma rays. Moreover, exposure of normal and AT fibroblasts to a dose of 8 Gy does not result in a significant inc rease in the fraction of apoptotic cells. Since this treatment reduces the clonogenic potential of human cells by at least two orders of mag nitude, we conclude that apoptosis is not the primary mechanism of cel l death induced by ionizing radiation in human normal and AT fibroblas t cultures. Therefore, our results are not in accordance with the curr ent hypothesis suggesting that increased radiosensitivity of AT cells is associated with deregulated apoptosis. (C) 1998 by Radiation Resear ch Society.