哺乳动物DNA甲基化（5mC）是一种非常重要的表观遗传修饰，TET蛋白氧化甲基化修饰的DNA，调节体内DNA甲基化的动态变化，进而调控多个重要生物学过程，其失调也导致多种疾病，尤其是肿瘤和白血病。TET蛋白本身，TET结合蛋白，底物（5mC）和三种产物（5hmC，5fC，5caC）组成复杂的生物分子体系，针对这一复杂分子体系的研究是目前表观遗传学领域最为活跃的研究方向。申请人前期解析了TET2-DNA复合物结构并初步阐明了TET蛋白识别底物的机制（Cell，2013，唯一通讯作者）。本项目拟在前期工作的基础上，围绕以TET蛋白为中心的复杂分子体系，利用上海光源生物大分子线站，进一步深入开展结构与功能研究。阐明TET蛋白的催化，底物识别及酶活性调节的分子机制，揭示TET蛋白结构与功能的关系及其在癌症发生过程中的致病机理，项目的开展也将为靶向TET蛋白的药物设计奠定理论基础。

DNA methylation is one of the most important epigenetic regulations. TET protein was found to be involved in DNA demethylation and plays an important role in various biological and pathological processes, including development of leukemia. TET protein, TET interacting proteins, 5mC (substrate) and 5hmC, 5fC, 5caC (products) form a complex biological system, which is the most active field in the research of epigenetic regulation..The applicant has determined the crystal structure of TET2 in complex with methylated DNA (Cell, 2013, the applicant is corresponding author). The structural and biochemical analyses indicate that the cys-rich domain wraps around the DSBH domain to stabilize the catalytic core. The methyl-Cytosine is flipped out of the DNA double helix and inserted into the catalytic cavity. TET2 specifically recognizes CpG dinucleotide and has no preference on its flanking sequence. Patient-derived TET2 mutation significantly decreased the enzymatic activity or the stability of TET2 protein. .This application was proposed based on these previous results and other unpublished preliminary data. The applicant wants to continue the studies on TET and TET associated biological system with the support of this grant and Shanghai Synchrotron Radiation Facility (SSRF). The research will focus on the molecular mechanisms of TET-mediated catalysis, substrate recognition, and regulation of enzymatic activity. The studies will also reveal how TET proteins are involved in the tumorigenesis and provide a structural basis for designing of specific inhibitors or activators for functional studies and potential therapeutic applications.