DNA损伤修复机制的研究，对于研究肿瘤的发生机制以及肿瘤治疗有实际意义。DNA损伤发生后，多种蛋白修饰参与DNA损伤应修复过程，比如蛋白泛素化、磷酸化等，我们前期发现OGT及O-GlcNAc蛋白糖基化修饰能被募集到DNA损伤位点并调控DNA损伤应答过程。有意思的是，OGT及O-GlcNAc糖基化修饰在多种肿瘤中水平异常，而且OGT能够O-GlcNAc糖基化修饰多种肿瘤相关蛋白，并影响蛋白稳定性或调控基因表达，参与肿瘤发生，暗示O-GlcNAc糖基化修饰在肿瘤发生中有作用。因此本项研究将以OGT及蛋白糖基化在DNA损伤应答中的作用为切入点，通过研究DNA损伤发生后OGT与蛋白泛素化的关系及OGT对表观遗传修饰的调控，发现OGT调控DNA损伤发生的关键分子，为使用OGT抑制剂治疗肿瘤提供分子依据，并探索OGT抑制剂和DNA损伤诱导类化疗药物联合用药治疗肿瘤的可行性。

O-linked N-acetylglucosamine linkage (O-GlcNAcylation) to Serine or threonine residues regulates numerous biological processes. Recently, we found that OGT and O-GlcNAcylation participate in gene transcription regulation and DNA damage response. OGT binds with TET2, which can recruit OGT to specific chromatin positions to O-GlcNAcylate H2B on Ser112. O-GlcNAcylated H2B could regulate the transcription of a specific group of genes. We also found that, in response to DNA damage, OGT reclocates to the sites of DNA damage to O-GlcNAcylate multiple DNA damage repair factors including H2AX and MDC1. Because aberrant OGT and O-GlcNAcylation have been found in multiple tumors including prostate cancer, breast cancer and leukemia etc, OGT might be a promising target for tumor treatment. In this proposal, we plan to explore the detailed mechanism, by which OGT and O-GlcNAcyltion participate in DNA damage response, and finally study whether we can combine OGT inhibitor and DNA damage inducing chemicals for tumor treatment. As protein ubiqutination happened in DNA damage response, we will first explore what is the role of O-GlcNAcylation in protein ubiquitination processes after DNA damage. Next, we will determine the epigenetic modification changes after DNA damage and elucidate the role of O-GlcNAcylation in this process. We will try to identify key factors in DNA damage response that are modified and regulated by OGT. As we have found that, following DNA damage, depletion of OGT prolongs the G2/M checkpoint and reduces cell viability, we finally want to study the effects of treatment with OGT inhibitor and DNA damage inducing chemicals on the viability of different type of tumor cells. We will analyze the functions and protein levels of the key factor regulated by OGT, and find the correlation between the sensitivity of tumor cells to the combined treatment and functions of these key factors. We believe that our study could identify key factors regulated by OGT following DNA damage and we could use these factors as predictive markers for precise treatment of tumors by OGT inhibitors and DNA damage inducing chemicals.