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  • Zhihao Zhuang, Professor

    Professor
    University of Delaware
    214 Drake Hall
    Newark, DE 19716
    (302) 831-8940
    http://sites.udel.edu/zhuanggroup/

    Biography

    (b. 1976) B.S., 1997, Sichuan University; Ph.D., 2003, University of New Mexico; Postdoctoral Fellow, 2003-2007, Pennsylvania State University

    Current Research

    Our research program is at the interface of chemistry and biology. Our current efforts are directed toward understanding protein posttranslational modification (PTM) by ubiquitin (Ub) and ubiquitin-like proteins (Ubl), particularly in the DNA damage tolerance. We focus on the function, structure and catalysis of the proteins and complexes involved in ubiquitination, deubiquitination and DNA damage tolerance. We also develop chemical approaches for protein ubiquitination and small molecule inhibitors that target a novel class of enzymes known as deubiquitinase (DUB). We address these research problems at a molecular level by employing a broad range of biochemical, biophysical, synthetic, and molecular and cell biology approaches.

    Chemical Protein Ubiquitination

    Enzymatic ubiquitination usually requires a number of enzymes, including ubiquitin ligase and the associated factors. The requirement of multiple enzymes limits the yield of enzymatic ubiquitination. Chemical ubiquitination circumvents the requirement of the ubiquitin enzyme cascade and can be readily adapted for modifying different target proteins. We develop chemical approaches for efficient protein ubiquitination. Currently we are exploring different chemical ligation strategies in conjunction with intein chemistry for site-specific protein ubiquitination. The chemically ubiquitinated proteins are used as probes to understand the molecular mechanism of cellular processes including DNA translesion synthesis. We are also developing ubiquitin-based probes for studying DUB’s ubiquitin-chain linkage specificity and target protein specificity.

    Regulation and Inhibition of Deubiquitinase

    DUBs antagonize the activity of ubiquitin ligases. Although the function of most human DUBs remains to be elucidated, it has become clear that the DUB activities are essential for the regulation of many cellular pathways. Abnormal cellular expression of DUBs or the loss of function due to mutation in certain DUB genes have been linked to various human diseases. The ubiquitin-specific proteases (USPs) constitute the largest family of DUBs. We are investigating the catalysis and regulation of DUBs that implicated in human diseases, including cancer, neurodegeneration and viral infection. Another goal of our study is to discover small molecule inhibitors against DUBs for therapeutic purposes. We also develop novel assays and platforms for identifying small molecule inhibitors of human DUBs.

    Molecular Mechanism of Eukaryotic DNA Damage Tolerance

    Posttranslational modification of proteins represents a crucial way of regulating cellular functions. We are investigating the eukaryotic DNA damage tolerance and its regulation by protein ubiquitination. Using the chemically ubiquitinated proliferating cell nuclear antigen (PCNA) as probes, we aim at deciphering the roles of the proteins and protein complexes involved in both the error-prone and error-free branches of DNA damage tolerance. We are particularly interested in how these processes are regulated by PCNA mono- and polyubiquitination. Our investigation will help to identify new players in the error-free branch of DNA damage tolerance and shed light on the inner workings of the eukaryotic DNA damage tolerance.

    Representative Publications

    • Paudel P, Zhang Q, Leung C, Greenberg HC, Guo Y, Chern YH, Dong A, Li Y, Vedadi M, Zhuang Z, Tong Y. Crystal structure and activity-based labeling reveal the mechanisms for linkage-specific substrate recognition by deubiquitinase USP9X PNAS (2019), 116(15):7288.

    • Gui W, Ott CA, Yang K, Chung JS, Shen S, and Zhuang Z. Cell-Permeable Activity-Based Ubiquitin Probes Enable Intracellular Profiling of Human Deubiquitinases. J. Am. Chem. Soc. (2018), 140(39):12424.

    • Gong P, Davidson GA, Gui W, Yang K, Bozza WP, Zhuang Z. Activity-based ubiquitin-protein probes reveal target protein specificity of deubiquitinating enzymes. Chemical Science. (2018), 9(40):7859.

    • Ott C, Baljinnyam B, Zakharov A, Jadhav A, Simeonov A, Zhuang Z. Cell Lysate-Based AlphaLISA Deubiquitinase Assay Platform for Identification of Small Molecule Inhibitors. ACS Chem Biol. (2017), 12(9):2399.

 

 

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  • Chemistry and Biochemistry
  • 102 Brown Laboratory
  • University of Delaware
  • Newark, DE 19716, USA
  • Phone: 302-831-1247
  • Undergraduate Program Inquiries 302-831-2465
  • chemistry@udel.edu