Low-Dose Hypersensitive Response for Residual pATM and γH2AX Foci in Normal Fibroblasts of Cancer Patients.

Abstract

To define the dose-response relationship for initial and residual pATM and γH2AX foci and temporal response of pATM foci in fibroblasts of 4 hyper-radiosensitivity (HRS)-positive cancer patients and 8 HRS-negative cancer patients and answer the question regarding the role of DNA double-strand break (DSB) recognition and repair in the mechanism of HRS. The cells were irradiated with single doses (0.1-4 Gy) of 6-MV X rays. The number of initial and residual pATM and γH2AX foci was assessed 1 hour and 24 hours after irradiation, respectively. Kinetics of DSB recognition and repair was estimated by pATM foci assay after irradiation with 0.2 and 2 Gy. Hyper-radiosensitivity response (confirmed by the induced-repair model) was clearly evident for residual pATM and γH2AX foci in fibroblasts of HRS-positive patients but not in fibroblasts of HRS-negative patients. Significantly less DSB was recognized by pATM early (10-30 minutes) after irradiation with 0.2 Gy in HRS-positive compared with HRS-negative fibroblasts. The present results provide evidence for the role of DSB recognition by pATM and repair in the mechanism of HRS and seem to support the idea of nucleo-shuttling of the pATM protein to be involved in HRS response.