For this, we determined if DMOG can protect MEFs lacking both the Suv39h1 and Suv39h2 methyltransferases. The ability of DMOG and CoCl2 to increase Hif1a levels was not altered in the SuvDKO MEFs. Further, whereas DMOG functioned as a radioprotector in normal MEFs, the protective effect of DMOG was significantly reduced in the SuvDKO MEFs. This indicates that the reduced ability of DMOG to protect SuvDKO MEFs may be attributed to both the loss of Hif1a dependent increase in the Suv39h1 methyltransferase, as well as changes in other Hif1a target genes. Overall, figure 5 demonstrates that DMOG can protect cells form radiation by stabilizing the Hif1a transcription factor, and increasing expression of genes, including the Suv39h1 methyltransferase, which can promote cell survival. Finally, we sought to determine if DMOG could protect cells from DNA damage at the level of the whole organism. Hif1a activation can transcriptionally activate a wide range of genes, including VEGF, which promote angiogenesis, and erythropoietin, which mobilizes bone marrow and improves blood parameters. It is likely that these factors may be important in promoting recovery of sensitive tissues, such as the bone marrow and gastrointestinal tract, from total body irradiation. In order to assess if the radioprotective effects of DMOG can be detected at the level of the whole organism, we examined if DMOG had protective effects in a murine total body irradiationmodel. DMOG was injected ip into either C57BL/6J or Balb/c mice, two widely used murine TBI model systems. DMOG alone did not cause any toxicity, with 100% of the mice surviving at 30 days, in agreement with previous studies using DMOG. TBI at 8Gy caused 80% and 100% lethality in saline-treated C57BL/6J and Balb/c mice respectively. However, DMOG treatment significantly improved the survival of both C57BL/6J and Balb/c mice and rescued them from radiation induced lethality. Activation of Hif1a by DMOG results in the transcriptional PR-171 upregulation of many genes and growth factors and is associated with increased cell survival in culture and protection of mice from whole body irradiation. These results clearly demonstrated that DMOG exhibits radioprotective potential in murine models. The Hif1a transcriptional regulatory protein controls the expression of genes which promote cell survival under conditions of low oxygen tension. Hif1a can switch cell metabolism towards increased expression of growth factors and anti-apoptotic factors as well as switching of metabolic pathways, allow the cell to maintain energy levels under hypoxic conditions. Hif1a levels are controlled through direct hydroxylation of Hif1a by the PHD2 prolylhydroxylase, leading to degradation of Hif1a under normal oxygen tension. Small molecule inhibitors of prolylhydroxylases have been developed which inhibit PHD2 and related enzymes, leading to stabilization of Hif1a and upregulation of the hypoxia response. Here, we have shown that stabilization of Hif1a using the prolylhydroxylase inhibitor DMOG protects both MEFs and mice from the cytotoxic effects of exposure to IR. This is consistent with previous studies high throughput screening demonstrating that tumor cells containing constitutively high levels of Hif1a are more resistant to both chemotherapy and radiotherapy. Increasing Hif1a levels in normal cells with prolylhydroxylase inhibitors such as DMOG therefore represents a novel pathway for the development of new and effective radioprotective agents. Our results clearly show that DMOG requires Hif1a to protect cells from radiation, since suppression of Hif1a with shRNA abolished the protective effect of DMOG.