DNA Damage Responses at Low Radiation Doses

Abstract

Increased cell killing after exposure to low acute doses of X rays (0-0.5 Gy) has been demonstrated in cells of a number of human tumor cell lines. The mechanisms underlying this effect have been assumed to be related to a threshold dose above which DNA repair efficiency or fidelity increases. We have used cells of two radioresistant human tumor cell lines, one that shows increased sensitivity to low radiation doses (T98G) and one that does not (U373), to investigate the DNA damage response at low doses in detail and to establish whether there is a discontinuous dose response or threshold in activation of any important mediators of this response. In the two cell lines studied, we found a sensitive, linear dose response in early signaling and transduction pathways between doses of 0.1 and 2 Gy with no evidence of a threshold dose. We demonstrate that ATM-dependent signaling events to downstream targets including TP53, CHK1 and CHK2 occur after doses as low as 0.2 Gy and that these events promote an effective damage response. Using chemical inhibition of specific DNA repair enzymes, we show that inhibition of DNA-PK-dependent end joining has relatively little effect at low (<1 Gy) doses in hyper-radiosensitive cells and that at these doses the influence of RAD51-mediated repair events may increase, based on high levels of RAD51/BRCA2 repair foci. These data do not support a threshold model for activation of DNA repair in hyper-radiosensitive cells but do suggest that the balance of repair enzyme activity may change at low doses.

Human Cytomegalovirus Disrupts both Ataxia Telangiectasia Mutated Protein (ATM)- and ATM-Rad3-Related Kinase-Mediated DNA Damage Responses during Lytic Infection

“…This cell line is semipermissive for HCMV infection (40), as would be expected given our previous results showing that p53 plays an important role in HCMV replication (11). Despite their mutagenic profile, T98G cells are capable of mounting a DSB damage response (81). G 0 -arrested T98G cells infected at an MOI of 5 with BrdU-labeled HCMV displayed labeled HCMV genomes in approximately 90% of the cell nuclei by 6 h p.i.…”

DNA damage-induced cell death: lessons from the central nervous system

“…In the autonomous pathways model, the DNA damagesignaling network activates DNA repair and cell death simultaneously and automatically, which is consistent with the current evidence [2,3,[7][8][9][10][11][12][13][14][15][16][17]. In this review, we will examine these two conceptual models for their capacity to explain DNA damage-induced cell death in the developing central nervous system (CNS) of rodents.…”

“…Generally speaking, cell death is a delayed response to DNA damage, resulting in elimination of the damaged cell ( Figure 1). The cell-protective and cell-destructive responses to DNA damage are downstream of a common signal transduction network that has been studied intensively in recent years ( Figure 1) (reviewed in Huen and Chen, in this issue) [2,3,[7][8][9][10][11][12][13][14][15][16][17]. While most protein components of this signaling network have been identified, the current knowledge does not explain when and why a damaged cell will choose to die.…”

Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice

“…These findings go in line with Short et al, who found that ATM-dependent signaling to downstream targets, such as TP53, CHK1 and CHK2, occurs even at low doses of 0.2 Gy IR. 35 In this regard, Suzuki et al 36 showed that the activated and phosphorylated ATM protein in the nucleus between doses of 10 mGy and 1 Gy is connected to multiple signal transduction pathways.…”