Because Hif1a functions as a transcriptional activator, it likely exerts its protective effects through increased expression of genes involved in DNA repair or cell survival. Previous studies indicate that hypoxia can alter expression of components of the mismatch repair pathway; however, altered expression of these proteins would not account for radioprotection observed after activation of Hif1a by DMOG. However, we identified 3 new targets for Hif1a – the CHD4 helicase, the MTA3 regulatory protein and the Suv39h1 methyltransferase. All 3 were increased at both the mRNA and protein level by DMOG and the hypoxia mimetic agent CoCl2. Previous work has shown that MTA1, a close family member related to MTA3, is also transcriptionally upregulated by Hif1a during hypoxia, implying that the MTA family of coactivators are a common target for the Hif1a transcription factor. Both CHD4 and MTA3 are components of the NuRD complex, a histone deacetylase complex which is implicated in DNA repair. Inactivation of CHD4 leads to increased sensitivity to IRinduced DNA damage, indicating a key role in the repair of DSBs. Taken together, this would suggest that increased levels of NuRD may protect cells from radiation. However, although Hif1a was important for DMOG to protect cells from IR, loss of either CHD4 or MTA3 expression did not alter sensitivity to IR in our cell system. We interpret this to mean that, although DMOG can stabilize Hif1a and increase levels of the NuRD complex, the accumulation of NuRD does not significantly impact the radiosensitivity of the cells. The accumulation of the NuRD deacetylase complex may therefore play an alternate role in the hypoxia response, such as transcriptional repression of genes during low oxygen tension. An alternate explanation for how DMOG may protect cells from radiation damage can be proposed based on the previous observation that Hif1a can alter expression of genes involved in the regulation of histone methylation. Hif1a increases expression of histone demethylases, including KDM4A and KDM4B, which function to remove methyl groups from methylated histones on the chromatin. The increased expression of KDMs during hypoxia is associated with a decrease in histone methylation, including a reduction on H3K9me3 levels. Previous work has shown that a decrease in H3K9me3 levels is associated with an increase in radiosensitivity. Hif1a -dependent increases in KDM expression would therefore be predicted to increase, XAV939 rather than decrease, radiosensitivity. However, we found that, unlike hypoxia, DMOG increased rather than decreased H3K9me3 levels. This result is explained by the fact that KDMs and Hif1a-prolylhydroxylases share a common catalytic mechanism, so that both classes of enzyme are inhibited by DMOG. DMOG therefore inhibits the Hif1a-prolylhydroxylase, leading to accumulation of transcriptionally active Hif1a and upregulation of KDMs. However, because DMOG can also directly inhibit KDMs, this essentially negates the increased expression of KDMs VE-821 moa mediated by Hif1a. Overall, DMOG will increase histone methylation through inhibition of KDMs.