Appropriate activation of DNA damage repair proteins is necessary for cell viability. DNA damage that is not repaired with high fidelity can lead to chromosomal aberrations or mitotic cell death. To date, it is unclear what factors control the ultimate fate of a cell receiving low levels of DNA damage (i.e. survival at the risk of increased mutation or cell death). We investigated whether DNA damage could be introduced into human cells at a level and frequency that could evade detection by cellular sensors of DNA damage. To study this we exposed both human colorectal and prostate cancer cells as well as normal human fibroblasts to equivalent doses of ionizing radiation delivered at either high dose rate (HDR) or at a continuous low dose rate (LDR). Following LDR exposures, we noted a reduction in the activation (phosphorylation) of the DNA damage sensor ATM and its downstream target H2AX as compared to HDR exposures. Surprisingly, this lack of DNA damage signaling was associated with increased amounts of cell killing following LDR exposures. This increased killing by LDR radiation has been previously termed the ‘inverse dose rate effect’ for which no clear molecular processes have been described. These LDR effects could be reduced by pre-activation of ATM or simulated in HDR-treated cells by inhibiting ATM function. Overall, these data demonstrate that DNA damage introduced at a reduced rate does not normally activate the DNA damage sensor ATM. Failure to normally activate ATM-associated repair pathways may contribute to the increased lethality of continuous LDR radiation, termed the inverse dose rate effect. These data provide a possible mechanism by which cells avoid accumulation of mutations as a result of error-prone DNA repair and may have broad-range implications for carcinogenesis and, potentially, the clinical treatment of malignancies.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]