Zhihao Zhuang, Professor
University of Delaware
214 Drake Hall
Newark, DE 19716
(b. 1976) B.S., 1997, Sichuan University; Ph.D., 2003, University of New Mexico; Postdoctoral Fellow, 2003-2007, Pennsylvania State University
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
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.
and Inhibition of Deubiquitinase
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.
Mechanism of Eukaryotic DNA Damage Tolerance
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.
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.
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.
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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