Rly, the biological responses to high- and lowdose IR are quite different in terms of their cell cycle effects. From studies of cataract incidence in astronauts, others have also concluded that low-dose IR can elicit such nonlinear biological responses in the lens [24]. This has also been reported for heart, small intestine, kidney and skin mouse tissues [49,65] and for human primary fibroblast cell lines [66]. Interestingly, in purchase LM22A-4 earlier studies on effects of high doses (more than 9 Gy) upon the rat eye lens, part of the irradiated lens was shielded and used to provide a baseline for cell proliferation. A dose of 340 mGy was calculated for the shielded portion when the whole lens was exposed to 9.6 Gy [64]. It is perhaps then not a coincidence that proliferation rates were also significantly increased in the shielded portion of those irradiated lenses [64]. These offer further support to the significant nonlinear biological responses to low-dose IR in the eye lens we have reported here.rsob.royalsocietypublishing.org Open Biol. 5:5.4. Double strand break repair, cell proliferation and the effect of low-dose ionizing radiation on the eye lensA mechanistic link between low-dose IR and the deficiencies in DSB repair and the increased proliferative response and increased levels of cyclin D1 of the epithelial cells in the periphery of the lens epithelium as observed in this study is plausible (figure 9). Cumulative DNA damage occurs with IR dose, but at low-dose IR this DNA damage triggers a retarded response to DSBs resulting in delayed repair Y-27632 site kinetics that is accompanied by re-entry into the cell cycle, evidenced by the elevated levels of cyclin D1 and increased cell density. It has been previously established that DSBs labelled by gH2AX caused by very low IR doses (1 mGy) are not as efficiently repaired as those sustained at higher IR doses [49,67]. Low (10 mGy) dose IR exposure also produces different transcriptional profiles compared with higher (more than 200 mGy) doses [49]. Such stochastic biological responses will be likely to increase with IR dose, but then they become limited by the cumulative DNA damage because this is linear with dose. In our schematic, cell proliferation peaks at about 500 mGy (figure 9) based on the best-fit nonlinear model of the lens aspect ratio data (figure 8d). This increase in cell proliferation at low IR doses will consequently preserve the irreversible changes associated with DNA damage, which would be expected to compromise the proliferative potential of these cells at the time of IR exposure (figure 7). At very high doses (15 Gy), it has long been known that in the first hours and first 3? days after IR exposure, all mitotic activity ceases [16], followed after by a short period (one week) of increased cell division before returning to preexposure levels [16]. We interpret these data to indicate that DNA repair is completed before any cell division is resumed5.3. Nonlinear effects upon the lens epitheliumIt is well established that cell proliferation ceases in the GZ of the lens epithelium after IR exposure (more than 15 Gy), causing a decrease in GZ cell density and the disorganization of cells in the TZ and MR within the peripheral region [16,56,57]. The effects on cell proliferation are probably due to IR-induced DNA damage causing TP53 stabilization, the induction of the CDK2 inhibitor p21 and the proteasomal degradation of cyclin D1 leading to G1/S phase cell cycle arrest [58,59]. Cyclin D1 is an.Rly, the biological responses to high- and lowdose IR are quite different in terms of their cell cycle effects. From studies of cataract incidence in astronauts, others have also concluded that low-dose IR can elicit such nonlinear biological responses in the lens [24]. This has also been reported for heart, small intestine, kidney and skin mouse tissues [49,65] and for human primary fibroblast cell lines [66]. Interestingly, in earlier studies on effects of high doses (more than 9 Gy) upon the rat eye lens, part of the irradiated lens was shielded and used to provide a baseline for cell proliferation. A dose of 340 mGy was calculated for the shielded portion when the whole lens was exposed to 9.6 Gy [64]. It is perhaps then not a coincidence that proliferation rates were also significantly increased in the shielded portion of those irradiated lenses [64]. These offer further support to the significant nonlinear biological responses to low-dose IR in the eye lens we have reported here.rsob.royalsocietypublishing.org Open Biol. 5:5.4. Double strand break repair, cell proliferation and the effect of low-dose ionizing radiation on the eye lensA mechanistic link between low-dose IR and the deficiencies in DSB repair and the increased proliferative response and increased levels of cyclin D1 of the epithelial cells in the periphery of the lens epithelium as observed in this study is plausible (figure 9). Cumulative DNA damage occurs with IR dose, but at low-dose IR this DNA damage triggers a retarded response to DSBs resulting in delayed repair kinetics that is accompanied by re-entry into the cell cycle, evidenced by the elevated levels of cyclin D1 and increased cell density. It has been previously established that DSBs labelled by gH2AX caused by very low IR doses (1 mGy) are not as efficiently repaired as those sustained at higher IR doses [49,67]. Low (10 mGy) dose IR exposure also produces different transcriptional profiles compared with higher (more than 200 mGy) doses [49]. Such stochastic biological responses will be likely to increase with IR dose, but then they become limited by the cumulative DNA damage because this is linear with dose. In our schematic, cell proliferation peaks at about 500 mGy (figure 9) based on the best-fit nonlinear model of the lens aspect ratio data (figure 8d). This increase in cell proliferation at low IR doses will consequently preserve the irreversible changes associated with DNA damage, which would be expected to compromise the proliferative potential of these cells at the time of IR exposure (figure 7). At very high doses (15 Gy), it has long been known that in the first hours and first 3? days after IR exposure, all mitotic activity ceases [16], followed after by a short period (one week) of increased cell division before returning to preexposure levels [16]. We interpret these data to indicate that DNA repair is completed before any cell division is resumed5.3. Nonlinear effects upon the lens epitheliumIt is well established that cell proliferation ceases in the GZ of the lens epithelium after IR exposure (more than 15 Gy), causing a decrease in GZ cell density and the disorganization of cells in the TZ and MR within the peripheral region [16,56,57]. The effects on cell proliferation are probably due to IR-induced DNA damage causing TP53 stabilization, the induction of the CDK2 inhibitor p21 and the proteasomal degradation of cyclin D1 leading to G1/S phase cell cycle arrest [58,59]. Cyclin D1 is an.