Anthony K.L. Leung Lab
Exploring the role of poly(ADP-ribose) in disease states and translating the findings to targeted drug discovery
About the Leung Lab
Our research program focuses on how gene regulation impacts diseases states, including cancer, neurodegeneration, and virus infection. We focus on how RNA biology is regulated by poly(ADP-ribose), or PAR.
We invent tools to investigate this protein modification, use a range of multi-disciplinary techniques to dissect the underlying mechanisms, and have discovered its roles in various processes. Our team is highly collaborative, drawing expertise from within the lab, the University, and around the world. We aim to translate our scientific findings to medicine.
Research Overview
Our research centers on ADP-ribosylation, a critical chemical modification ubiquitous across all biological kingdoms. ADP-ribosylation influences key biological processes like DNA repair, RNA synthesis, and protein translation, and disruptions are associated with disease. Despite its biological significance, ADP-ribosylation remains poorly understood.
Our lab aims to fill the gaps in understanding the roles of ADP-ribosylation in RNA processes, RNA virus infection, and the formation of biomolecular condensates such as stress granules. We have pioneered new tools for investigating and manipulating ADP-ribosylation, from single-molecule techniques to proteomics. Using these tools, we discovered that this modification is a potent inducer of a specific type of protein condensation that is known to be associated with cancer and neurological diseases, and showed that stress granules can be remodeled by ADP-ribosylation removal during virus infection. Finally, we propose that the biological functions of ADP-ribosylation are governed by parameters such as site, length, and structure—a concept we term the “PAR code hypothesis,” which we aim to uncover and decode.
PAR Structural Properties
Anthony Leung's lab has teamed up again with Sua Myong's lab and discovered unexpected structural properties of poly(ADP-ribose). PAR is a nucleic acid-like molecule that regulates crucial cellular processes through protein modification, and can be a scaffold of molecular complexes. This study, led by postdoc Mohsen Badiee, revealed that PAR chains maintain rigidity until reaching a certain salt concentration, then abruptly compact, unlike DNA and RNA, which gradually become more compact as the concentration increases.
The team also looked at the response to FUS, a PAR-binding protein with positively charged domains. Previously they discovered that PAR is a potent trigger of FUS condensation. Here they showed that increasing FUS concentrations triggered the switch from stiff to compact PAR. In contrast, a different PAR-binding protein did not alter PAR stiffness.
These findings imply that a given PAR molecule can adopt various shapes based on environmental factors and provides insights into how proteins interact with PAR. Expanding our understanding of PAR’s structural behavior is important to untangling its role in normal cellular processes and in diseases like cancer and neurodegenerative diseases.
Switch-like compaction of poly(ADP-ribose) upon cation binding, Badiee M, Kenet AL, Ganser LR, Paul T, Myong S*, Leung AKL*, PNAS, 2023. *co-corresponding authors.
Selected Publications
Badiee M, Kenet AL, Ganser LR, Paul T, Myong S*, Leung AKL*. Switch-like compaction of poly(ADP-ribose) upon cation binding. PNAS, 2023. *co-corresponding authors
Rhine K, Dasovich M, Yoniles J, Badiee M, Skanchy S, Ganser LR, Ge Y, Fare CM, Shorter J, Leung AKL*, Myong S*. Poly(ADP-ribose) drives condensation of FUS via a transient interaction. Molecular Cell, 2022. *co-corresponding authors
Dasovich M, Beckett MQ, Bailey S, Ong SE, Greenberg MM, Leung AKL. Identifying Poly(ADP-ribose)-Binding Proteins with Photoaffinity-Based Proteomics. Journal of the American Chemical Society, 2021.
Jayabalan AK, Adivarahan S, Koppula A, Abraham R, Batish M, Zenklusen D, Griffin DE, Leung AKL. Stress granule formation, disassembly, and composition are regulated by alphavirus ADP-ribosylhydrolase activity. PNAS, 2021.
Fischer JW, Busa VF, Shao Y, Leung AKL. Structure-Mediated RNA Decay by UPF1 and G3BP1. Molecular Cell, 2020.
Ando Y, Elkayam E, McPherson RL, Dasovich M, Cheng SJ, Voorneveld J, Filippov DV, Ong SE, Joshua-Tor L, Leung AKL. ELTA: Enzymatic Labeling of Terminal ADP-Ribose. Molecular Cell, 2019.
How to Join the Leung Lab
The Leung Lab members join us through different pathways. Common ways to join the lab are below.
PhD Students
The Leung Lab is part of several PhD training programs at Johns Hopkins University. Visit the websites below to learn more about the specifics of each program and the admissions process. All programs provide full tuition and stipend support. The Leung lab usually accepts one PhD student per year.
Master's Students
The Leung lab hosts students from the Department of Biochemistry and Molecular Biology Master of Health Science and Master of Science programs. If you are a student in either program and are interested in the Leung lab, you should contact Anthony Leung by email. If you are not a BMB master's student but would like to be, check out the links above to find out more.
Undergraduate Students
Johns Hopkins University undergraduate first-years, sophomores, and juniors interested in research opportunities should contact Anthony Leung by email.
Postdoctoral Fellows
We are seeking highly motivated individuals with a background in biochemistry, biophysics, synthetic chemistry, structural biology, or RNA virus to join our lab. Knowledge of polynucleotides, including DNA, RNA, or poly(ADP-ribose), or of macromolecular post-translational modifications, such as ubiquitin or SUMO, are preferred.
Interested candidates should send a cover letter describing their career goals/research plan (0.5-1 page) and accomplishments (0.5 page) to Anthony Leung. The candidate's CV and contact information for three references should also be provided. In addition to training within our lab, the Biochemistry and Molecular Biology Department has an active postdoctoral training program.