Evasion of early cellular response mechanisms following low level radiation-induced DNA damage.
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 achieve this, we exposed cells to equivalent doses of ionizing radiation delivered at either a high dose rate (HDR) or a continuous low dose rate (LDR). We observed reduced activation of the DNA damage sensor ataxia-telangiectasia mutated (ATM) and its downstream target histone H2A variant (H2AX) following LDR compared with HDR exposures in both cancerous and normal human cells. This lack of DNA damage signaling was associated with increased amounts of cell killing following LDR exposures. Increased killing by LDR radiation has been previously termed the "inverse dose rate effect," an effect for which no clear molecular processes have been described. These LDR effects could be abrogated by the preactivation of ATM or simulated in HDR-treated cells by inhibiting ATM function. These data are the first to demonstrate that DNA damage introduced at a reduced rate does not activate the DNA damage sensor ATM and that failure to activate ATM-associated repair pathways contributes to the increased lethality of continuous LDR radiation exposures. This inactivation may reflect one strategy by which cells avoid accumulating mutations as a result of error-prone DNA repair and may have a broad range of implications for carcinogenesis and, potentially, the clinical treatment of solid tumors.
Collis
Spencer J
SJ
Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Schwaninger
Julie M
JM
Ntambi
Alfred J
AJ
Keller
Thomas W
TW
Nelson
William G
WG
Dillehay
Larry E
LE
Deweese
Theodore L
TL
D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage / Q000502:physiology* / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D006657:Histones / Q000528:radiation effects; D006801:Humans; D011839:Radiation, Ionizing
C468783:H2AX protein, human; D006657:Histones; D002738:Chloroquine; D004247:DNA