https://www.leunglab.org/publication daily 0.75 2024-01-29 https://www.leunglab.org/join-us daily 0.75 2021-05-08 https://www.leunglab.org/lablife daily 0.75 2022-12-03 https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/754778f7-d0ce-4361-a86b-3cae889cb16a/IMG_8958.jpg Lab Life https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/748d0632-d59c-4404-bca6-354d49c988ea/IMG_8292.jpg Lab Life https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/462e3b36-d1e8-4f6b-b07b-c0a175adba4a/_JHU5883.jpg Lab Life Developing COVID-19 drug https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/b9f2ee5f-453e-42ef-9801-199e464edf68/IMG_2635.jpg Lab Life https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/96a06f67-a78b-4da5-9a04-5f978c1b3fc3/145551350_4312164542130270_5477803375225181468_n.jpg Lab Life 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of Wisconsin-Madison! With thanksgiving hearts, we say farewell to our postdoc Mohsen @MohBadiee. Thanks for all that you have done in mentoring and lab operation, on top of the foundational science you have discovered and techniques developed on poly(ADP-ribose)! All the best at University of Wisconsin-Madison! https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/6146235c-d3b7-405c-9705-8e5327128b37/stm.jpg News - Sep 14: Is Poly(ADP-ribose) (PAR) the missing piece for protein condensation in neurological disorders? We are excited to collaborate with @HopkinsMedicine team led by Zhang and Rothstein looking into PAR’s role in promoting toxicity of C9ORF72 repeats in ALS/FTD. PhD candidate Morgan Dasovich and MHS alum Chen co-authored paper, Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins, is now published in Science Translational Medicine. Congratulations! Click here to read the article. Gao, J., Mewborne, Q. T., Girdhar, A., Sheth, U., Coyne, A. N., Punathil, R., . . . Zhang, K. (2022). Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins. Science Translational Medicine, 14(662), eabq3215. doi:10.1126/scitranslmed.abq3215. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/f3e828e7-8506-40e3-b3ef-e05b8b185c8b/FYTqB_cWQAAA7Rh.jpeg News - Jun 22: Lab families and friends social gathering for mini golf & laser-tag We celebrated for the start of our new antiviral-drug project and welcoming new people! https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/20eb208c-e4c8-4d35-a113-9a09cea01643/Screen+Shot+2022-08-09+at+5.29.29+PM.png News - Jun 20: ELTA is used in DNA ADP-ribosylation in Nature Microbiology paper! Out now: The DarTG toxin-antitoxin system provides phage defence by ADP-ribosylating viral DNA. By Michele LeRoux , Michael Laub & colleagues. Congrats to their team! LeRoux, M., Srikant, S., Teodoro, G. I., Zhang, T., Littlehale, M. L., Doron, S., ... & Laub, M. T. (2022). The DarTG toxin-antitoxin system provides phage defence by ADP-ribosylating viral DNA. Nature Microbiology, 1-13. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/ebb58a12-1601-42b1-9078-58171495ca52/1-s2.0-S0166354222001139-ga1_lrg.jpg News - May 25: Two new SARS-CoV-2 macrodomain publications with our collaborators appeared online Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening Click here to read the article. Design, synthesis and evaluation of inhibitors of the SARS-CoV-2 nsp3 macrodomain Click here to read the article. Roy, A., Alhammad, Y. M., McDonald, P., Johnson, D. K., Zhuo, J., Wazir, S., ... & Fehr, A. R. (2022). Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening. Antiviral Research, 105344. [Abstract/PDF] Sherrill, L. M., Joya, E. E., Walker, A., Roy, A., Alhammad, Y. M., Atobatele, M., ... & Ferraris, D. (2022). Design, synthesis and evaluation of inhibitors of the SARS-CoV-2 nsp3 macrodomain. Bioorganic & Medicinal Chemistry, 116788. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/0b6cf182-2977-46b9-8791-400feb32be4c/FTd_TTIVUAEKcwL.jpeg News - May 23: Congratulations to Veronica for her wonderful thesis defense! Bon chance to her next journey in @Fertig Lab! https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/3ccb2f87-b583-42a0-a19e-3c808b44673d/FTPTGVwWAAADGvk.jpeg News - May 20: The lab played bowling to say goodbye to two fantastic scientists (and amazing bowlers) — Veronica and Ming! All the best with their new adventures in Germany and California! https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/05c8d3bc-58bb-45dd-98a1-b9c26a9ed560/FR1rFh_XwAMM4Ug.jpeg News - May 4: Anthony speaks at the ACS webinar: The Conserved Macrodomain is a Novel Therapeutic Target of Coronaviruses The ACS (American Chemical Society) Chemistry at the Frontline of Coronavirus webinar features the authors of the most highly read and cited articles in ACS biological and analytical chemistry journals that shed light on aspects of SARS-CoV-2 and the COVID-19 pandemic. Click here to read the article. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/3a40684f-dcbf-4484-834f-e93b09f29a64/FQ4rRjeVcAAgqgL.jpeg News - Apr 21: Our backstory (and struggles) in developing a new class of antivirals against COVID and other viral diseases is featured in Hopkins Bloomberg Public Health Magazine We recently developed tools to find inhibitors to an enzyme used by some viruses—including coronaviruses—during infection, to identify compounds with the potential to become antivirals for Covid-19 as well as future coronaviruses. Click here to read the article. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/349f991c-2644-4654-815f-4b2fbd5f20c6/FPmLYNhVcAMQqdw.jpeg News - Apr 5: Leung lab received the Addgene Blue Flame Award This award serves to recognize researchers who have at least one plasmid deposited at Addgene that has been distributed more than 100 times. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1510f2c9-95d8-4256-9ce9-caf46d3c36f3/FPJQBAeWYAUXiO8.jpeg News - Mar 30: Anthony chaired the kick-off session of the @CSHL PARP Family and ADP-ribosylation meeting Cold Spring Harbor Laboratory, NY https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/a3be2e7d-1fe1-4778-a000-23489bb593c6/FNBsYuWXsAE1dcN.jpeg News - Mar 3: Our article on PAR as a potent trigger for FUS condensates is featured in Molecular Cell Do you know protein condensation can be triggered with a tiny amount of biomolecules? With Myong lab, we found that poly(ADP-ribose) (PAR) is a potent trigger for condensing FUS, a key protein involved in neurodegeneration. Click here to read the article. Rhine, K., Dasovich, M., Yoniles, J., Badiee, M., Skanchy, S., Ganser, L. R., ... & Myong, S. (2022). Poly (ADP-ribose) drives condensation of FUS via a transient interaction. Molecular cell, 82(5), 969-985. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/9978c27f-edc5-42c3-a735-7faf9dd96366/cb1c00721_0004.jpeg News - December 14: Macrodomain inhibitor screening story was published in ACS Chemical Biology and selected as ACS Editors’ Choice Do you know it is possible to develop COVID19 drug besides polymerase or protease inhibitors? And this potential drug target is conserved in all human and animal coronaviruses as well as all SARS-CoV-2 variants (e.g., Delta and Omicron). We target macrodomain—a coronaviral enzyme critical for viral replication and disease progression. In our latest study, we develop a high-throughput platform to identify drugs that inhibit SARS-CoV-2 macrodomain. Our versatile platform enables us to identify drugs that inhibit SARS-CoV-2 and MERS-CoV macrodomains, but not their closest human counterpart to avoid potential unwanted side effects. Therefore, we may be able to develop a viral specific drug to treat COVID, MERS & more… The cool thing about macrodomain as a drug target is that it is also critical for the replication and pathogenesis of alphaviruses — another virus with pandemic potential as recently defined by The National Institute of Allergy and Infectious Diseases (NIAID). Dasovich, M., Zhuo, J., Goodman, J. A., Thomas, A., McPherson, R. L., Jayabalan, A. K., ... & Leung, A. K. (2021). High-throughput activity assay for screening inhibitors of the SARS-CoV-2 Mac1 Macrodomain. ACS chemical biology, 17(1), 17-23. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/93cfbece-c35e-4408-be00-86a53050df13/Abstract+booklet_FEBS+AdvCourse2021.png News - November 10: PhD candidate Morgan Dasovich speaks at FEBS Advanced Lecture Course 2021 “Cellular Stress and ADP-ribosylation” Morgan discusses his latest work on poly(ADP-ribose) as a potent trigger of protein condensation. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1632493561070-5806LS9VSMZDOD347E2N/Screen+Shot+2021-09-24+at+10.25.52+AM.png News - September 24: Anthony speaks at JHU Chemistry–Biology Interface Annual Retreat Dr. Leung discusses our journey from Proteomics to COVID-19 Therapeutics Development @CbiJhu. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1632494372164-JM9C9MN7V9CVJW96ORHE/Screen+Shot+2021-09-24+at+10.39.23+AM.png News - August 26: XDBio PhD student Hongrui Liu joins our lab Hongrui, from Tsinghua University, was selected as one of the first cohorts in the pioneering PhD program XDBio at Johns Hopkins. This exciting new program emphasizes individualized training and interdisciplinary research. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1632493249173-TCNG83Z1FVY4MKNUT8CN/Screen+Shot+2021-09-24+at+10.04.11+AM.png News - August 9: Post-Doctoral Fellow, Dr. Aravinth Jayabalan, is selected as a 2021 Forbeck Scholar The Forbeck Scholar Award annually selects junior clinical or post-doctoral fellows with high levels of scientific achievement. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1632494538780-R8HG9R93VEUGFHTZ9VRL/Screen+Shot+2021-09-24+at+10.42.09+AM.png News - July 29: A new consensus agreed by leaders in academia and industry on the nomenclature for ADP-ribosyltransfereases PARP is now a name by itself, not an acronym, to refer this enzyme class. Click here to read the article. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1632493073042-G35GI8K6MQ0Q4LNHUKR9/Screen+Shot+2021-09-24+at+10.17.42+AM.png News - July 26: Anthony speaks at American Chemical Society Seminar Series Dr. Leung shares our surprise findings on how poly(ADP-ribose) serves as a potent trigger of protein condensation. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1632492904222-QV21UN9UHH2JJGSUQDPK/Screen+Shot+2021-09-24+at+10.14.55+AM.png News - July 14: PhD candidate Shang-Jung received the Crawford Award The Crawford Award recognizes the achievements of a PhD student in academics, research, and service at the JHSPH BMB. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1632492718055-NJ5LQ7CJ31O4M2UW9XSM/Screen+Shot+2021-09-24+at+10.11.36+AM.png News - July 1: PhD candidate Isabel Uribe received NIH F31 Predoctoral Fellowship Many congrats to @CbiJhu PhD candidate Isabel Uribe @IsabelRUribe for receiving @NIH F31 Predoctoral Fellowship @NIGMS! https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1632492263935-H1I885341ZL8Q1QTVBOM/Screen+Shot+2021-09-24+at+10.04.11+AM.png News - June 15: Aravinth and Morgan present at FASEB NAD+ Conference Aravinth discusses his latest findings on a class of viral enzymes removing ADP-ribosylation that is critical for replication and virulence. PhD candidate Morgan Dasovich will also present his JACS work on the first chemical probe in identifying the poly(ADP-ribose) binding proteome. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619913272228-KJ3O2OZPLXOXEFUIP4OT/_JHU5857.jpg News - May 7: Seminar on Chemoenzymatic Strategies for Exploring ADP-ribosylation Ph.D. candidate Morgan Dasovich presents our work in the 13th Annual Frontiers in Chemistry and Biology Interface Symposium. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619986377092-3WRLAGK79XDW14R5745Z/ExifOX_WEAEvFXZ.jpeg News - April 15: Seminar on tools to dissect poly(ADP-ribose) code Herbert Irving Comprehensive Cancer Center, Columbia University https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619986201384-5WMNGFS71JV1PRHDLWPZ/ExbhwYVWYAIwg5i.jpeg News - April 14: Seminar on compositional control of cellular condensates by ADP-ribosylation Genome Science Institute, Boston University https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619990882319-H7G8G7HQGO8PP3BPPM2G/MUSC-Banner.png News - March 25: Seminar on ADP-ribosylation in biomolecular condensates Department of Biochemistry and Molecular Biology, Medical University of South Carolina https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619986027335-3CZWET012NFWL2Q06KEF/Ev_hdtoXEAAJT-P.jpeg News - March 8: Review on Circular RNA structure Our lab's latest review by grad student Veronica Busa on how RNA structure impacts circular RNA biology. This review aims to clarify what special considerations are needed in identifying, measuring, and generating structured circRNAs for investigating the RNA structure in the biogenesis, function and degradation of circRNAs. Busa VF, Leung AKL. Thrown for a (stem) loop: How RNA structure impacts circular RNA regulation and function. Methods. 2021 Mar 2:S1046-2023(21)00064-5. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619976841384-XTATYZ98V7YWA7D10LDJ/Isabel_winner.jpeg News - February 25: Ph.D. candidate Isabel Uribe received 2021 Elsa Orent Keiles Fellowship in Biochemistry The award was established in 1996 with a bequest from the estate of Elsa Orent Keiles, a 1925 ScD graduate of the Department of Chemical Hygiene (now Biochemistry & Molecular Biology). The department has used this generous gift to recognize a Ph.D. candidate who has excelled academically and in the laboratory and who has otherwise distinguished themselves as an outstanding example for his/her fellow students. Besides academic excellence, Isabel was also noted for her efforts in leading the Diversity and Inclusion Initiative in the Department and University. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619985212448-P00WN5RCA75KANEN59WZ/210216_TOC_graphic-01.png News - February 17: PARprolink to identify PAR-binding proteome Ph.D. candidate Morgan Dasovich published his work in JACS paper describing the first chemical probe to identify direct binders of poly(ADP-ribose) (PAR). Our census of the PAR-binding proteome revealed that these 743 direct binders are enriched in various biomolecular condensates (stress granules, nucleoli and DNA repair foci). Using specific probes, we identified dozens of proteins that prefer binding to long over short PAR length. These data further support the PAR code hypothesis, where poly(ADP-ribose) directs condensate formation in cells. Dasovich M, Beckett MQ, Bailey S, Ong SE, Greenberg MM, Leung AKL. Identifying Poly(ADP-ribose)-Binding Proteins with Photoaffinity-Based Proteomics. J Am Chem Soc. 2021 Mar 3;143(8):3037-3042. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619578878462-S0RRM1UJ3FINX0EJNPG9/_JHU5578.jpg News - February 15: Anthony recognized as a finalist of the 2021 President's Frontier Award President’s Frontier Award recipients are selected via an annual university-wide competition for demonstrating significant scholarly achievement and showing exceptional promise for important future work. https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619984436402-1JTQ2OOKF7HK9HEWJ1FF/SG_split+channel_Color.gif News - February 5: Macrodomain ADP-ribosylhydrolase activity disrupts stress granules Postdoctoral fellow Aravinthkumar Jayabalan discovered how alphaviruses direct the compositional control of cellular condensates during infections through their nsP3 enzymes to remove ADP-ribosylation—an activity that is critical for viral replication and virulence. nsP3 not only breaks down stress granules through its macrodomain ADP-ribosylhydrolase activity, but also forms another class of condensates through its hypervariable domain. These condensates lack translation factors but contain other stress granule components (e.g., G3BP1). Our data suggest that the nsP3 breaks down the protein–ADP-ribose–protein network within stress granules so that the translation factors and viral RNAs are released for selective translation of viral proteins. Given that Nature selects ADP-ribosylation as a target in dissolving stress granules, our findings may provide a new therapeutic avenue to disassemble stress granule-like aggregates in neurodegenerative diseases. e.g., those induced by ALS mutations. 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. Proc Natl Acad Sci U S A. 2021 Feb 9;118(6):e2021719118. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619983687964-W4IUY6TCJDBUC9I14ZNY/EtLbZ9xWMAABPZq.jpeg News - February 1: A decade at Johns Hopkins Today we celebrate our lab's 10th anniversary. We thank past and present members for making the lab a fun place to work, breaking grounds into new scientific horizons, and being kind. Excited to see how the current team will shape our science for the next 10 years! https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619983408811-F6LLMGXLPUJYTVBCEYA7/ADP-ribose+and+analogues+bound+to+the+deMARylating+macrodomain+from+the+bat+coronavirus+HKU4+copy.png News - January 12: Bat coronavirus macrodomain structure and biochemistry characterized Our collaborative work is published with the Johnson lab from the University of Alabama at Birmingham, where Ph.D. graduate Lyle McPherson discovered that a conserved activity to remove ADP-ribosylation is present in bat, from which many coronaviruses (e.g., SARS-CoV-2) originate. Hammond RG, Schormann N, McPherson RL, Leung AKL, Deivanayagam CCS, Johnson MA. ADP-ribose and analogues bound to the deMARylating macrodomain from the bat coronavirus HKU4. Proc Natl Acad Sci U S A. 2021 Jan 12;118(2):e2004500118. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619986993745-U2AFX2SP1AOBHVHPPN1S/1604410216773.jpeg News - January 8: ADPriboDB 2.0 released Our ADPriboDB 2.0 paper is out Nucleic Acids Research documenting a new version of our ADP-ribosylated substrate database—48,346 entries | 9,097 proteins | 32,946 sites. In this new version, we provide a new tool to visualize structural and functional contexts surrounding the modified site. Hope this database would be useful for uncovering new PARP biology! Using ADPriboDB 2.0, we discovered that ADP-ribosylated substrates are significantly associated with the human interactors of proteins encoded by #SARS_CoV_2, which encodes a conserved protein domain called macrodomain that binds and removes ADP-ribosylation, regulating tRNA and rRNA metabolism. Ayyappan V, Wat R, Barber C, Vivelo CA, Gauch K, Visanpattanasin P, Cook G, Sazeides C, Leung AKL. ADPriboDB 2.0: an updated database of ADP-ribosylated proteins. Nucleic Acids Res. 2021 Jan 8;49(D1):D261-D265. 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RNA virus - Macrodomain ADP-ribosylhydrolase is critical for viral replication and virulence Macrodomain is a relatively small protein fold consisting of ~150 amino acids which has been identified in humans and pathogens, including all coronaviruses. Most macrodomains bind to the small molecule ADP-ribose and ADP-ribosylated proteins. Recent data revealed that a subset of macrodomain in humans and viruses possesses enzymatic activity to hydrolyze ADP-ribose from ADP-ribosylated proteins. For example, these enzymatically active macrodomains are present in a subset of positive-stranded RNA viruses, including coronaviruses, alphaviruses, rubella virus, and hepatitis E virus. The ability to bind and remove ADP-ribose is critical for viral replication and virulence, making macrodomain an attractive antiviral target. Dasovich M, Zhuo J, Goodman JA, Thomas A, McPherson RL, Jayabalan AK, Busa VF, Cheng SJ, Murphy BA, Redinger KR, Alhammad YMO, Fehr AR, Tsukamoto T, Slusher BS, Bosch J, Wei H, Leung AKL. High-Throughput Activity Assay for Screening Inhibitors of the SARS-CoV-2 Mac1 Macrodomain. ACS Chem Biol. 2021 Dec 14 [Abstract/PDF] 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. Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1666-1671. [Abstract/PDF] Leung AKL, McPherson RL, Griffin DE. Macrodomain ADP-ribosylhydrolase and the pathogenesis of infectious diseases. PLoS Pathog. 2018 Mar 22;14(3):e1006864. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1620158544826-F91C15P4FBCJ25BUFB9B/RGB_short.gif Home - RNA virus - Virus disrupts stress granules by removing ADP-ribosylation We discovered that alphaviruses direct the compositional control of cellular condensates during infections through macrodomain to remove ADP-ribosylation. Macrodomain ADP-ribosylhydrolase not only breaks down stress granules but also forms another class of condensates that lack translation factors but contain other stress granule components (e.g., G3BP1). These data suggest that the virus breaks down the protein–ADP-ribose–protein network within stress granules so that the translation factors and viral RNAs are released for selective translation of viral proteins. 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. Proc Natl Acad Sci U S A. 2021 Feb 9;118(6):e2021719118. [Abstract/PDF] https://www.leunglab.org/work/par-condensates monthly 0.5 2021-05-11 https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1620325305973-20VAJSPA26C5QY81BPUJ/HeLa.jpg Home - PAR condensates - Poly(ADP-ribose) in Stress Granules We discovered that poly(ADP-ribose), or PAR, is critical for the formation of stress granules—a class of biomolecular condensates enriched with mRNA translation factors and implicated in viral infection, cancer chemotherapeutic resistance and neurodegeneration. We are investigating the regulatory mechanisms behind these disease states, with the goal of turning our actionable targets into therapeutic applications. Leung AK, Vyas S, Rood JE, Bhutkar A, Sharp PA, Chang P. Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Mol Cell. 2011 May 20;42(4):489-99. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1620403283218-UGSO1X90MQ9Z2MFP349A/TiCB+Figure3.001.jpeg Home - PAR condensates https://www.leunglab.org/work/rna-regulation monthly 0.5 2021-05-11 https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1620423155057-8RQ8CFISI1GGL3007PBP/20210506_Chromatin+workshop.jpg Home - RNA regulation - RNA metabolism regulated by ADP-ribosylation Since its discovery in 1963, ADP-ribosylation has been implicated in regulating fundamental DNA metabolic processes, including DNA repair, in the nucleus. Little is known about the role of ADP-ribosylation in RNA metabolism or in the cytoplasm. While investigating the role of microRNAs in stress, we previously found that the core microRNA-binding protein Argonaute (Ago) is PARylated and such PARylation reduces microRNA activities. Our recent analyses further revealed that PAR-binding proteins are significantly associated with RNA metabolism, such as splicing and translation. Using novel tools, we are investigating the mechanism of how ADP-ribosylation regulates Argonaute and other RNA-binding proteins. Leung AK, Vyas S, Rood JE, Bhutkar A, Sharp PA, Chang P. Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Mol Cell. 2011 May 20;42(4):489-99. [Abstract/PDF] Dasovich M, Beckett MQ, Bailey S, Ong SE, Greenberg MM, Leung AKL. Identifying Poly(ADP-ribose)-Binding Proteins with Photoaffinity-Based Proteomics. J Am Chem Soc. 2021 Mar 3;143(8):3037-3042. [Abstract/PDF] https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1620423727078-RB43SXTL6HJUC176QU2A/Slide1.jpeg Home - RNA regulation - Structure-mediated RNA decay (SRD) regulated by essential stress granule factor G3BP1 RNA encodes information both in its nucleotide sequence and folded structure. RNA sequence has been determined genome-wide, but most structures remain uncharacterized in cells. We recently made an unexpected discovery that reframes the current understanding of how RNA is degraded. We discovered a pathway that recognizes overall RNA structuredness as a signal for degradation—a new paradigm to read RNA. This Structure-mediated RNA decay (SRD) requires two double-stranded (ds)RNA binding proteins UPF1, which is central for coordinating mRNA decay pathways, and its associated protein G3BP1. UPF1 cannot regulate highly-structured mRNAs or noncoding RNAs, such as circular RNA, without G3BP1—the essential component of stress granules. Therefore, G3BP1 is the primary regulator of SRD. Based on computational and experimental analyses, we estimated that this decay pathway regulates one-third of all human genes. We are investigating SRD rules, mechanisms and biology. Fischer JW, Busa VF, Shao Y, Leung AKL. Structure-Mediated RNA Decay by UPF1 and G3BP1. Mol Cell. 2020 Apr 2;78(1):70-84.e6. [Abstract/PDF] https://www.leunglab.org/work/par-technology monthly 0.5 2021-05-11 https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1620432114490-ASQFSMA0G23YNH6ESPNB/MassSpec2.jpg Home - PAR technology https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619986993745-U2AFX2SP1AOBHVHPPN1S/1604410216773.jpeg Home - PAR technology https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1620432685693-B6QWYP6LIK6LU2YK6HWQ/Label.jpg Home - PAR technology https://images.squarespace-cdn.com/content/v1/60877fab5523717fb05596fe/1619985212448-P00WN5RCA75KANEN59WZ/210216_TOC_graphic-01.png Home - PAR technology