解析化学修饰对生物大分子凝集和相变过程的调控机制与生物功能是化学生物学研究的重要内容。申请人研究化学修饰调控蛋白功能的成果发表在Nature (2019)和Molecular Cell (2019,2017)。.DNA拓扑异构酶TOP2A剪切和打开DNA双螺旋需经过连续的六个步骤，而相变形成的封闭环境可能有利于以上步骤的进行。TOP2A的C末端存在丰富的磷酸化修饰及促成相变的无序结构域，但是TOP2A磷酸化修饰与相变的因果关系尚未解析。申请人发现TOP2A与代谢酶UGDH相互作用，缺失UGDH的细胞中TOP2A磷酸化水平和相变能力均升高。UGDH的代谢物UDP-GlcUA则干扰TOP2A相变。申请人拟通过结构解析、高分辨成像技术和生物信息学等技术，解析UDP-GlcUA结合并调控TOP2A磷酸化，进而干扰TOP2A相变的机制，阐明相变对TOP2A的重要作用并奠定化学干预基础。

Analyzing the regulatory mechanism and biological function of chemical modification on the aggregation and phase transition of biological macromolecules is an important direction for basic research in life sciences. Applicants' researches on metabolite-mediated protein activity were published in Nature (2019) and Molecular Cell (2019,2017)..TOP2A requires six consecutive steps to cut and open the DNA double helix. We speculate that the relatively closed and stable environment provided by the phase transition may be beneficial to the above steps. At the same time, there are a large disordered region and abundant phosphorylation modifications in the TOP2A C terminus, but the relationship between TOP2A phosphorylation modification and phase transition has not been resolved. The applicant found that TOP2A interacts with UGDH and the level of phosphorylation and TOP2A phase transition are increased in cells lacking UGDH. The metabolite of UGDH, UDP-GlcUA interferes with the phase change of TOP2A. .The applicant intends to analyze the mechanism of UDP-GlcUA binding and regulating TOP2A phosphorylation through structural analysis and high-resolution imaging technology, combined with molecular biology and bioinformatics, and clarify the mechanism of TOP2A phase transition during drug resistance. It plays an important role in laying a new foundation for chemical intervention.