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 (0.1-4Gy) of 6-MV X rays. The number of initial and residual pATM and γH2AX foci was assessed 1hour and 24hours after irradiation, respectively. Kinetics of DSB recognition and repair was estimated by pATM foci assay after irradiation with 0.2 and 2Gy. 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 (10-30minutes) after irradiation with 0.2Gy 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.