Zhihao Zhuang, assistant professor in the Department of Chemistry and Biochemistry at the University of Delaware, has won the National Science Foundation (NSF) Faculty Early Career Development Award.
It is NSF's most prestigious award in support of faculty early in their careers who exemplify the role of teacher-scholars through outstanding research, excellent education, and the integration of education and research within the context of the mission of their organizations.
Zhuang's five-year, $783,000 award will support an integrated research and outreach program focusing on the development of new chemical methods for efficiently bonding ubiquitin, the so-called "kiss of death" protein, to proliferating cell nuclear antigen (PCNA), a key protein in DNA replication and repair, and exploring at the molecular level how cells bypass damaged DNA in a process called translesion synthesis.
Besides the celebrated role of ubiquitin as a molecular tag for labeling proteins to be chopped up by the cell's "waste disposal" or proteasome, for which the 2004 Nobel Prize in Chemistry was awarded, ubiquitin and ubiquitin-like proteins have since been shown to play essential roles in a myriad of fundamentally important cellular processes.
Research in the rapidly expanding area of DNA damage response has been stimulated largely by the seminal findings that the bonding of ubiquitin and small ubiquitin-like modifier (SUMO) to PCNA controls precisely how eukaryotic cells respond to different types of DNA damage and how the different repair or tolerance pathways are chosen to cope with that damage.
Zhuang's team has been investigating the molecular mechanism of translesion synthesis in the model organism Saccharomyces cerevisiae (more commonly known as baker's yeast or budding yeast), which has proven to be extremely useful in understanding many essential cellular processes in eukaryotes, the domain of life that includes higher-order organisms such as humans, animals, and plants.
"What we learn from the model system, S. cerevisiae, has important implications for the human system because many of the DNA transaction pathways in both organisms are conserved," Zhuang notes. "We expect that the knowledge we gain from this study will contribute to the further deciphering of ubiquitin's role in how cells respond to damaged DNA. Moreover," he adds, "we expect that the new chemical approaches we develop for producing ubiquitylated proteins will aid researchers in investigating other cellular processes that involve post-translational modification by ubiquitin or ubiquitin-like proteins."
Zhuang's laboratory works at the interface of chemistry and biology to develop new tools and approaches that will enable better understanding of complex biological systems at the molecular level.
"Currently we are working to dissect the different steps in the process of translesion synthesis with a focus on the role of ubiquitin modification," Zhuang says. "Our findings from this investigation will further inform our ongoing research on human cancer development and therapy."
The NSF award will support the expansion of Zhuang's research collaborations at home and abroad. Kelvin Lee, Gore Professor of Chemical Engineering and director of the Delaware Biotechnology Institute, will share his expertise in mass spectrometry. The project also will foster a long-term research collaboration with the Institute of Genetics at the Hungarian Academy of Sciences.
The ultimate goal of the project, Zhuang notes, is to establish research and educational programs that not only advance the field of chemical biology by enhancing the scientific understanding of DNA damage tolerance, but also to inspire and educate the next generation of chemical biologists.
The project's outreach component seeks to spark the scientific curiosity and career aspirations of high-school students, with particular emphasis on underrepresented minorities in chemistry and biology, through the virtual reality visualization system called the "CAVE" at the Delaware Biotechnology Institute.
"High-school students will be able to walk into the larger-than-life 3-D structures of the specialized DNA polymerases that we are studying to see the variations in geometry of the active site as well as the DNA binding groove. This will help them to understand how the remarkable polymerases tolerate damaged DNA," Zhuang says.
Key collaborators in Zhuang's outreach effort include Doug O'Neal, manager at Delaware Biotechnology Institute, and biology teacher Thomas Fleetwood and his students at the Charter School of Wilmington.
"I'm very excited and honored to receive this award," Zhuang says. "There are lots of things to accomplish in both the research and outreach programs, and we are looking forward to making progress on both ends. I also want to extend my thanks to my students and coworkers for their great effort and contribution. This would not have been possible without their hard work." There are currently five graduate students and one postdoctoral fellow working in Zhuang's laboratory.
A new method for producing ubiquitylated proteins developed by Zhuang and his group recently was reported in the prestigious journal Nature Chemical Biology. Zhuang also recently won a Delaware Health Sciences Alliance (DHSA) pilot project grant for research to discover inhibitors that can lead to the development of potent, new anti-cancer drugs.
Source: University of Delaware