3 years ago

Low-dose hypersensitive response for residual pATM and γH2AX foci in normal fibroblasts of cancer patients

In our previous study, using flow cytometry-based clonogenic survival assay, we demonstrated low-dose hyper-radiosensitivity (HRS) effect in normal fibroblasts of 4 of the 25 cancer patients investigated. In the present study, we define the dose-response relationship for initial and residual pATM and γH2AX foci and temporal response of pATM foci in fibroblasts of the 4 HRS-positive patients and 8 HRS-negative patients and answer the question regarding the role of DNA double strand break (DSB) recognition and repair in the mechanism of HRS. Methods and Materials The cells were irradiated with single doses (0.1 - 4 Gy) of 6MV 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. Results HRS 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 to HRS-negative fibroblasts. Conclusions The present results provide the evidence for the role of DSB recognition by pATM and repair in the mechanism of HRS and seem to support the idea of nucleoshuttling of the pATM protein to be involved in HRS response.

Teaser

We demonstrate, for the first time, low-dose hypersensitive response for both residual pATM and γH2AX foci in normal fibroblasts of 4 HRS-positive patients and its lack in fibroblasts of 8 HRS-negative patients. We also show that in HRS-positive fibroblasts not all DSB are recognized by pATM early after irradiation with low dose. The data provide the evidence for the role of DSB recognition by pATM and repair in the mechanism of HRS.

Publisher URL: www.sciencedirect.com/science

DOI: S0360301617340695

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