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Anthony K. L. Leung
Anthony K. L. Leung
Biochemistry, Molecular Biology, Bloomberg SPH
Molecular Biology and Genetics
615 N. Wolfe Street
Baltimore, MD 21205
RNA and poly(ADP-ribose) biology in virus infection and cancer
We are RNA biologists interested in the interaction between gene and environment.
In human genome, only 5% encodes for proteins while most are transcribed as non-coding RNAs (previously thought to be junk DNA). We are interested in two classes of non-coding RNAs – microRNAs and circular RNAs (circRNAs). We recently found that, during stress that is common in cancers and viral infection, microRNA activities and other RNA metabolic processes are regulated by a "druggable" post-translational modification called ADP-ribosylation and PARPs – the enzymes that makes ADP-ribosylation. Given that PARP inhibitors have shown promise in treating cancers, neurodegenerative diseases and ischemia, we are actively exploring the role of poly(ADP-ribose) regulation in microRNA activities in these diseases.
RNA metabolism in cancers and viral infection: MicroRNA literally means short RNAs—though small in size, microRNAs constitute a sizeable class of gene regulators (~2000 in humans), and collectively regulate at least 60% of protein-coding gene expression. On the other hand, circRNAs has the shape of a circle instead of a typical linear string. There are at least 25,000 different circRNAs in humans and one of them has been demonstrated to be critical for developing brain properly. However, much about this class of RNAs is still unknown. Our lab is investigating the molecular mechanism on how ADP-ribosylation regulates microRNA activities and other RNA metabolism.
Develop tools to investigate ADP-ribosylation: Though ADP-ribosylation has been discovered for more than 55 years, it has been challenging to answer mechanistic questions without knowing where the endogenous sites of modification are. Previously, ADP-ribosylation sites could only be inferred by mutagenesis, but the deficiency of ADP-ribosylation in such site-specific mutants can also be explained by secondary effects. Recently, our lab has successfully developed a non-biased proteomics approach to identify ADP-ribosylation sites at all classes of amino acids at the proteome level inside cells. In addition, our lab also recently developed the first publicly available database of ADP-ribosylated proteins (ADPriboDB) for researchers inside and outside the field to appreciate the complexity and breadth of this therapeutically important protein modification. We are actively developing new tools to investigate this interesting modification that also behaves like a polynucleotide, such as DNA and RNA.
ADP-ribosylation hydrolase and RNA viruses: Our lab recently found that a subset of RNA viruses encodes a protein module called macrodomain that removes (hydrolyzes) ADP-ribosylation. Using Chikungunya alphavirus as a model, we found that mutant viruses abrogating such ADP-ribosylhydrolase activity are not viable whereas mutants reducing the activity have slower replication in mammalian cells and reduced virulence in mice. The macrodomain in the chikungunya virus is similar in other alphaviruses, none of which have a cure or treatment. This specific group of viruses includes the Venezuelan equine encephalitis virus (which U.S. officials consider a potential bioterrorist threat) and the Mayaro virus, which Scientific American magazine has dubbed the “next Zika” for its pandemic potential. The macrodomain is also similar in all coronaviruses, which includes those that cause Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Finding a treatment for one could greatly improve the ability to treat or prevent the others. Our long-term goal is to understand the fundamentals of how macrodomain works in virus infection and other biological contexts.
Leung AKL, McPherson RL, Griffin DE. Macrodomain ADP-ribosylhydrolase and the pathogenesis of infectious diseases. PLoS pathogens. 2018; 14(3):e1006864.
Leung AKL. PARPs. Current biology 2017; 27(23):R1256-R1258. Fischer JW, Leung AK. CircRNAs: a regulator of cellular stress. Critical reviews in biochemistry and molecular biology. 2017; 52(2):220-233.
McPherson RL, Abraham R, Sreekumar E, Ong SE, Cheng SJ, Baxter VK, Kistemaker HA, Filippov DV, Griffin DE, Leung AK. ADP-ribosylhydrolase activity of Chikungunya virus macrodomain is critical for virus replication and virulence. PNAS 2017; 114(7):1666-1671.
Vivelo CA, Wat R, Agrawal C, Tee HY, Leung AK. ADPriboDB: The database of ADP-ribosylated proteins. Nucleic acids research. 2017; 45(D1):D204-D209.
Daniels CM, Ong SE, Leung AK. The Promise of Proteomics for the Study of ADP-Ribosylation. Molecular Cell. 2015; 58(6):911-24.
Daniels CM, Ong SE, Leung AK. Phosphoproteomic approach to characterize protein mono- and poly(ADP-ribosyl)ation sites from cells. Journal of proteome research. 2014; 13(8):3510-22.
Leung AK. Poly(ADP-ribose): an organizer of cellular architecture. The Journal of cell biology. 2014; 205(5):613-9.
Leung AK, Vyas S, Rood JE, Bhutkar A, Sharp PA, Chang P. Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Molecular Cell. 2011; 42(4):489-99.
Leung AK, Young AG, Bhutkar A, Zheng GX, Bosson AD, Nielsen CB, Sharp PA. Genome-wide identification of Ago2 binding sites from mouse embryonic stem cells with and without mature microRNAs. Nature structural & molecular biology. 2011; 18(2):237-44.
Leung AK, Sharp PA. MicroRNA functions in stress responses. Molecular Cell. 2010; 40(2):205-15.
Leung AK, Calabrese JM, Sharp PA. Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules. PNAS 2006; 103(48):18125-30.