Paul M. Lieberman, Ph.D.
The Wistar Institute
3601 Spruce Street
Philadelphia, PA 19104
Professor and Program Leader, Gene Expression and Regulation Program
Director, Center for Chemical Biology and Translational Medicine
Contribution to Science
1. Basic Mechanism of Transcription Regulation. My early scientific work focused on basic mechanisms of gene activation. Using viral transcription factors we discovered novel interactions between TFIIA and TFIID that induce conformational changes in the interaction with TATA box and downstream binding sites. This change is what constituted a weak from strong promoter. We now know that this change confers higher activation and release of RNA polymerase II from start sites, and accounts for major changes in transcription levels in response to sequence specific transcription factors.
- Kao, C. C., Lieberman, P. M., Schmidt, M. C., Zhou, Q., Pei, R. and Berk, A. J. 1990.Cloning of a transcriptionally active human TATA binding factor. Science 248, 1646-1650.
- Lieberman, P. M. and Berk A J. 1994. A mechanism for TAFs in transcriptional activation: activation domain enhancement of TFIID-TFIIA-Promoter DNA complex formation. Genes and Development 8, 995-1006.
- Ozer, J., Moore, P. A., Bolden, A. H., Lee, A. H., Rosen, C. A., and Lieberman, P. M. Molecular cloning of the small (gamma) subunit of human TFIIA reveals functions critical for activated transcription. Genes Dev. 19: 2324-2335.
- Chi, T., Lieberman, P., Ellwood, K., and Carey, M. A general mechanism for transcriptional synergy by eukaryotic activators. Nature 377; 254-257.
2. Epigenetic regulation of oncogenic viruses. The oncogenic herpesviruses Epstein-Barr Virus (EBV) and Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) persist as minichromosomes in viral-associated cancer cells. The viral genomes express a minimal number of viral genes required for oncogenesis, but the mechanisms that control viral gene expression and viral chromosome persistence in cancer cells is not fully understood. We have used functional genomics, molecular genetics, and structural biochemistry method to investigate mechanisms of viral gene regulation, including analysis of viral transcription factors, chromatin assembly, histone modifications, chromosome conformation, and viral chromosome transmission. We have also studied how viruses perturb epigenetic mechanisms to provides viral infected cells with carcinogenic potential.
- Lamontagne RJ, Soldan SS, Su C, Wiedmer A, Won KJ, Lu F, Goldman AR, Wickramasinghe J, Tang HY, Speicher DW, Showe L, Kossenkov AV,Lieberman PM. 2021. A multi-omics approach to Epstein-Barr virus immortalization of B-cells reveals EBNA1 chromatin pioneering activities targeting nucleotide metabolism. 17(1):e1009208. PMID:33497421.
- Kim KD, Tanizawa H, De Leo A, Vladimirova O, Kossenkov A, Lu F, Showe LC, Noma KI,Lieberman PM. 2020. Epigenetic specifications of host chromosome docking sites for latent Epstein-Barr virus. Nat Commun.;11(1):877. PMID: 32054837.
- Huang H, Deng Z, Vladimirova O, Wiedmer A, Lu F, Lieberman PM, Patel DJ. 2016. Structural basis underlying viral hijacking of a histone chaperone complex. Nat Commun. 7:12707. PMID: 27581705
- Arvey, A., Tempera, I., Tsai, K., Chen, H.S., Tikhmyanova, N., Klichinsky, M., Leslie, C., and Lieberman, P.M. 2012. An atlas of the Epstein-Barr Virus transcriptome and epigenome reveals host-viral regulatory interactions. Cell Host Microbe 12:233-45.
3. Epigenetic regulation of telomeric chromatin. Telomeres are protective structures at the end of chromosomes that require specialized chromatin and replication for their maintenance. Although telomeric chromatin is thought to be heterochromatic, the telomere and subtelomere are highly dynamic nucleoprotein structures that have a major impact on overall genome stability. We have studied human telomere chromatin and its dynamic regulation by the non-coding telomere-encoded repeat RNA (TERRA) on the function of telomere telomeric chromatin, replication, and innate immune signaling.
- Mei Y, Deng Z, Vladimirova O, Gulve N, Johnson FB, Drosopoulos WC, Schildkraut CL, Lieberman PM. 2021. TERRA G-quadruplex RNA interaction with TRF2 GAR domain is required for telomere integrity. Sci Rep. ;11(1):3509. .PMID:33568696
- Beishline K, Vladimirova O, Tutton S, Wang Z, Deng Z, Lieberman PM. 2017. CTCF driven TERRA transcription facilitates completion of telomere DNA replication. Nat Commun. 8(1):2114. PMID: 29235471
- Tutton S, Azzam GA, Stong N, Vladimirova O, Wiedmer A, Monteith JA, Beishline K, Wang Z, Deng Z, Riethman H, McMahon SB, Murphy M, Lieberman PM. 2016. Subtelomeric p53 binding prevents accumulation of DNA damage at human telomeres. EMBO J. 35(2):193-207. PMID: 26658110
- Deng Z, Kim ET, Vladimirova O, Dheekollu J, Wang Z, Newhart A, Liu D, Myers JL, Hensley SE, Moffat J, Janicki SM, Fraser NW, Knipe DM, Weitzman MD, Lieberman PM. 2014. HSV-1 remodels host telomeres to facilitate viral replication. Cell Rep. 9(6):2263-78. PMID: 25497088.
4. Mechanisms of oncogenic herpesvirus latency and persistence. Human oncogenic herpesviruses encode specialized viral proteins dedicated to maintaining the viral genomes during latent and persistent infection. These proteins have unique structural features, including DNA binding and cryptic endonucleolytic activity required for replication termination and chromosome. Segregation. These factors also control chromatin-assembly, replication origin activity, and epigenetic programming, They represent attractive targets for anti-viral intervention.
- Dheekollu J, Wiedmer A, Ayyanathan K, Deakyne JS, Messick TE, Lieberman PM. 2021. Cell-cycle-dependent EBNA1-DNA crosslinking promotes replication termination at.oriP and viral episome maintenance. Cell. 184(3):643-654.e13. PMID:33482082
- Vladimirova O, De Leo A, Deng Z, Wiedmer A, Hayden J, Lieberman PM. 2021. Phase separation and DAXX redistribution contribute to LANA nuclear body and KSHV genome dynamics during latency and reactivation. PLoS Pathog.17(1):e1009231..PMID:33471863.
- De Leo A, Deng Z, Vladimirova O, Chen HS, Dheekollu J, Calderon A, Myers KA, Hayden J, Keeney F, Kaufer BB, Yuan Y, Robertson E, Lieberman PM. 2019. LANA oligomeric architecture is essential for KSHV nuclear body formation and viral genome maintenance during latency. PLoS Pathog. 15(1):e1007489. PMID: 30682185.
- Chen HS, De Leo A, Wang Z, Kerekovic A, Hills R, Lieberman PM. 2017. BET-Inhibitors Disrupt Rad21-Dependent Conformational Control of KSHV Latency. PLoS Pathog. 13(1):e1006100. PMID: 28107481
5. Small molecule drug discovery. We have established multiple different approaches to identify small molecule inhibitors and regulators of EBV and KSHV infection and tumorigenesis. These include assay development for high-throughput screening, structure-guided fragment-based drug design, computationally directed drug design, and phenotypic assay development and screening. We have used these to target EBV latency protein EBNA1, KSHV latency protein LANA, lytic inducing pathways for EBV, and identification of targets for bioactive small molecules. Development of new small molecules with better understanding of target interaction is a major focus for future research, with great potential for therapeutic impact.
- Messick TE, Smith GR, Soldan SS, McDonnell ME, Deakyne JS, Malecka KA, Tolvinski L, van den Heuvel APJ, Gu BW, Cassel JA, Tran DH, Wassermann BR, Zhang Y, Velvadapu V, Zartler ER, Busson P, Reitz AB, and Lieberman PM. 2019. Structure-based design of small molecule inhibitors of EBNA1 DNA-binding blocks Epstein-Barr virus latent infection and tumor growth. Sci Transl Med. 11(482). PMID:30842315.
- Tikhmyanova N, Tutton S, Martin KA, Lu F, Kossenkov AV, Paparoidamis N, Kenney S, Salvino JM, Lieberman PM. 2017. Small molecule perturbation of the CAND1-Cullin1-ubiquitin cycle stabilizes p53 and triggers Epstein-Barr virus reactivation.PLoS Pathog.Jul 17;13(7):e1006517. doi: 10.1371/journal.ppat.1006517. PMID: 28715492 PMCID: PMC5531659.
- Tikhmyanova N, Schultz DC, Lee T, Salvino JM, Lieberman PM. 2013. Identification of a new class of small molecules that efficiently reactivate latent Epstein-Barr virus. 2013. ACS Chem Biol. 2013 Sep 12. [Epub ahead of print] PMID: 24028149.
- Li N, Thompson S, Schultz DC, Zhu W, Jiang H, Luo C, Lieberman PM. 2010. Discovery of selective inhibitors against EBNA1 via high throughput in silico virtual screening. PLoS One;5(4):e10126.
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