THE P53-MEDIATED DNA-DAMAGE RESPONSE TO IONIZING-RADIATION IN FIBROBLASTS FROM ATAXIA-WITHOUT-TELANGIECTASIA PATIENTS

Purpose: To assess the functionality of the p53-mediated pathway, acti vated by the ataxia-telangiectasia gene product (ATM) in response to i onizing radiation, in cells derived from four ataxia-without-telangiec tasia patients. These patients exhibit cerebellar ataxia and cellular abnormalities that are compatible with the diagnosis of ataxia-telangi ectasia (AT), but the telangiectasias normally seen in AT patients are absent. Materials and method: Protein and RNA extracts were prepared from primary fibroblast cultures non- or exposed to 5 Gy of ionizing r adiation in order to monitor the modulation in p53 and ATM protein lev els by immunologic techniques and WAF1/Cip1(p21) mRNA by Northern blot ting. Results: A sub-optimal response in terms of increased levels of p53 and the transcriptional activation of WAF1/Cip1(p21) was seen in t he ataxia-without-telangiectasia fibroblast cultures examined over a 4 h period post-irradiation when compared with normal fibroblast cultur es. The ATM protein was expressed at much reduced levels in the ataxia -without-telangiectasia and the classical AT fibroblast cultures exami ned when compared with normal fibroblast cultures. Conclusions: Despit e the milder clinical phenotypes observed in these ataxia-without-tela ngiectasia patients and the presence of low levels of ATM protein in t he fibroblast cultures, their response to ionizing radiation quantitat ively resembles that reported in fibroblast cultures established from classical AT patients.