Associated with increased radiosensitivityand decreased genomic stability. Secondly, DMOG can also increase the expression of Suv39h1 Nutlin-3 through activation of Hif1a, a process which will also tend to increase H3K9me3 levels. Importantly, the ability of DMOG to function as a radioprotector was significantly reducedin MEFs which lacked expression of Suv39h1 and Suv39h2. Since DMOG increases Suv39h1 expression through a Hif1a dependent mechanism, this indicates that the main contributor to DMOG mediated radioresistance is the transcriptional upregulation of the Suv39h1 methyltransferase by Hif1a. How can increased expression of Suv39h1 impact radiosensitivity? As discussed above, cells lacking Suv39h1 have significant defects in both H3K9me3 and in DSB repair. DMOG may therefore increase expression of Suv39h1, leading to increased methylation of H3K9 and allowing for more efficient activation of the DNA damage response. Suv39h1 may therefore methylate H3K9 within specific regions of the chromatin after DNA damage in order to improve the efficiency of repair. However, it is also possible that the radioprotective effects of increased Suv39h1 are not directly on the DNA repair machinery, but instead feedback through altered methylation of key genes, such as Axitinib VEGFR/PDGFR inhibitor anti-apoptotic proteins. Overall, the protective effect of DMOG is largely mediated through the Hif1a dependent increase in expression of the Suv39h1 methyltransferase, leading to increased H3K9me3 levels in the cell. Finally, we also demonstrated that when DMOG was given to mice prior to irradiation it can protect them from total body irradiation. Significant improvement in survival was found in 2 different mouse strains, underlining the effectiveness of DMOG in a whole animal model. Previous studies using DMOG and related prolylhydroxylase inhibitors in whole animal models have indicated protection from ischemic injury, protection in a murine model of colitisand the development of hypoxia tolerance. A key target of Hif1a are the growth factors VEGF and erythropoietin. DMOG can detectably increase erythropoietin levels in animal models, leading to improvement in blood parameters, and can act to increase angiogenesis and muscle recovery from ischemic injury. The most sensitive tissues to IR are the GI tract and bone marrow. The ability of DMOG to stimulate the production of factors such as erythropoietin and VEGF, which can stimulate repopulation of the hematopoietic progenitors and promote formation of new vasculature, are likely to be critical factors in the ability of DMOG to protect whole animals from radiation. Effective radioprotectors and radiation-mitigating agents are needed in the clinic to treat the radiation victims and to protect individuals from radiation exposure resulting from nuclear disasters or radiological attack. Many small molecules, including anti-oxidants, cytokines, activators of NF-KappaB and cyclindependent kinase inhibitors have been shown to have radioprotective effects in murine TBI models. Our studies demonstrate that the prolyl hydroxylase inhibitor DMOG is an effective radioprotector in both tissue culture and whole animal models. Activation of Hif1a evokes a complex response at both the cellular and whole organism levels. Changes in gene transcription caused by DMOG at the cellular level, including changes in histone methylation, can impact the ability of individual cells to repair and survive radiation exposure. In addition, the ability of DMOG to stabilize Hif1a and stimulate production of growth factors such as VEGF and erythropoietin can promote DNA repair, the repopulation of sensitive cell types and promote survival at both the level of individual tissues and the whole organism.