High and Low Fluences of a-Particles Induce a G1 Checkpoint in Human Diploid Fibroblasts

The effects of exposure to high and very low fluence a-particles on the G1 checkpoint were investigated in human diploid fibroblasts irradiated and released from density-inhibited confluent cultures by the use of the cumulative labeling index method. Transient and permanent arrests in G1 occurred in fibroblast populations exposed to mean doses as low as 1 cGy, suggesting that nontraversed bystander cells may contribute to the low dose response. In cells exposed to high fluences, the G1 checkpoint is at least as extensive as in g-irradiated cells. In contrast to g-irradiated cells, neither repair of potentially lethal damage nor a reduction in the fraction of cells transiently or permanently arrested in G1 were observed in cells held in confluence for 6 h after a-particle irradiation. Studies with isogenic wild-type, p53, and p21 mouse embryo fibroblasts exposed to either g or a-particle radiation revealed a total lack of G1 arrest in either p53 –/– or p21 cells, indicating that the G1 checkpoint in wild-type cells is p53-dependent and that p21 fully mediates the role of p53 in its induction. In contrast to human cells, mouse embryo fibroblasts do not undergo a permanent G1 arrest. Except under conditions favoring potentially lethal damage repair, a comparable expression pattern of p53, p21, and other cell cycle-regulated proteins (pRb, p34, and cyclin B1) was observed in a-particle or g-irradiated human fibroblasts.