Summary Although targeted therapies have transformed medical oncology, traditional cytotoxic chemotherapeutics remain one of the primary cancer treatments. Toxicity to normal tissues, the renewable tissue in particular continues to represent major challenge in the clinic. Effective strategies of normal tissue protection are in great need for reducing the side effects and thus improving cancer patient’s quality of life. We recently uncovered a novel mechanism by which p53-regulated MDM2 functions together with MDMX to govern DNA damage sensitivity by targeting EZH2 for degradation. As a histone methyltransferase, EZH2 promotes H3K27me3 and therefore chromatin compaction to protect DNA. We showed that interference of the association between MDM2 and MDMX could stabilize EZH2, resulting in protection of renewable tissues from DNA damage agents-induced acute injury. Based on these findings, we propose to test the hypothesis that the MDM2/MDMX complex can be targeted for EZH2 stabilization and thereby for normal tissue chemotherapy protection. The deliverable of this proposal is to establish a novel strategy of targeting MDM2/MDMX-regulated EZH2 to selectively protect normal cells. Additionally, the proposal will develop the pharmacological approach and has already identified lead compounds. Therefore the success of our proposed studies would pave the way of targeting MDM2/MDMX- regulated EZH2 for chemotherapy protection to the clinic, promising a great potential to enhance the efficacy of chemotherapy and to improve patient quality of life.