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, activated by the ataxia-telangiectasia gene product (ATM) in response to ionizing radiation, in cells derived from four ataxia-without-telangiectasia patients. These patients exhibit cerebellar ataxia and cellular abnormalities that are compatible with the diagnosis of ataxia-telangiectasia (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 radiation in order to monitor the modulation in p53 and ATM protein levels by immunologic techniques and WAF1/Cip1(p21) mRNA by Northern blotting.

RESULTS

A sub-optimal response in terms of increased levels of p53 and the transcriptional activation of WAF1/Cip1(p21) was see in the ataxia-without-telangiectasia fibroblast cultures examined over a 4 h period post-irradiation when compared with normal fibroblast cultures. The ATM protein was expressed at much reduced levels in the ataxia-without-telangiectasia and the classical AT fibroblast cultures examined when compared with normal fibroblast cultures.

CONCLUSIONS

Despite the milder clinical phenotypes observed in these ataxia-without-telangiectasia patients and the presence of low levels of ATM protein in the fibroblast cultures, their response to ionizing radiation quantitatively resembles that reported in fibroblast cultures established from classical AT patients.