RONEN MARMORSTEIN – PH.D.

Professor, Department of Biochemistry and Biophysics
Investigator, Abramson Family Cancer Research Institute

Faculty Website

http://www.med.upenn.edu/biocbiop/faculty/marmorstein/

Contact Information

The Perelman School of Medicine at the University of Pennsylvania
Department of Biochemistry and Biophysics
454 BRB II/III
421 Curie Blvd, Philadelphia, PA 19104-6161
Office: 215-898-7740
Fax: 215-746-5511
marmor@upenn.edu

Publication Links

Research Interest

The Marmorstein laboratory uses a broad range of molecular, biochemical and biophysical research tools centered around X-ray crystal structure determination to understand the chemical basis for the epigenetic regulation of gene expression. The laboratory is particularly interested in gene regulatory proteins and their upstream signaling kinases that are aberrantly regulated in cancer and other age-related disorders such as obesity and Alzheimer’s disease, and the use of high-throughput small molecule screening and structure-based design strategies towards the development of protein-specific small-molecule probes of protein function and for development into therapeutic agents.

Contributions to Science

My laboratory has pioneered the structure-function analysis of histone acetyltransferases (HATs) and continues to make seminal contributions in this area. Specifically, my laboratory determined the first crystal structure of a type A HAT and characterized its mechanism of catalysis, and the first to describe the mode of histone substrate binding by a HAT. We have continued to characterize the molecular basis for HAT function demonstrating that these enzymes fall into sequence-divergent subfamilies with structurally conserved core regions and structurally divergent flanking regions and catalytic mechanisms that serve to contribute to their diverse biological properties. Given that HATs mediate many biological processes including cell cycle progression, dosage compensation, repair of DNA damage, and hormone signaling; and that aberrant HAT function has also been correlated with several human diseases including solid tumors, leukemias, inflammatory lung disease, viral infection, diabetes, fungal infection and drug addiction, they have become important drug targets and our studies have contributed to the development of HAT inhibitors.

  • Rojas, J. R., Trievel, R. C., Mo, Y., Li, X., Zhou, J., Berger, S. L., Allis, C. D. and Marmorstein, R. Crystal Structure ofTetrahymena GCN5 Bound with Coenzyme-A and Histone H3 peptide. (1999) Nature401:93-97. PMID: 10485713
  • Yan, Y, Harper, S, Speicher, D. and Marmorstein, R. The Catalytic Mechanism of the Yeast Esa1 Histone Acetyltransferase Involves a Self-Acetylated Intermediate. (2002)Nature Structural Biology 11:862-869. PMID: 12368900
  • Liu, X., Wang, L., Zhao, K., Thompson, P. R. Hwang, Y., Marmorstein, R. and Cole, P. A. The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. (2008)Nature 451:846-850. PMID: 18273021 URL: http://dx.doi.org/10.1038/nature06546
  • Yuan, H., Rossetto, D., Mellert, H., Dang, W., Srinivasan, M., Johnson, J., Hodawadekar, S., Ding, E. C., Speicher, K., Abshiru, N., Perry, R., Wu, J., Yang, C., Zheng, Y.G., Speicher, D. W., Thibault, P., Verreault, A., Johnson, F. B., Berger, S. L., Sternglanz, R., McMahon, S. B., Côté, J. and Marmorstein, R. MYST protein acetyltransferase activity requires active site lysine autoacetylation. (2011)EMBO J. 31:58-70. PMID: 22020126 URL: http://dx.doi.org/10.1038/emboj.2011.382

My laboratory has extended our molecular and enzymology studies to the broader family of N- acetlyltransferases including the non-histone lysine acetyltrasnferases (KATs) and the N-amino acetyltransferases (NATs). We have uncovered important molecular signatures that distinguish HATs, KATs and NATs. Acetylomic studies have revealed that thousands of proteins in many cellular organelles are lysine acetylated and the majority of eukaryotic proteins are acetylated on their N-termini in a cotranslational process.   Together, these acetylation events mediate diverse biological process including cellular apoptosis, enzyme regulation, protein localization, rDNA transcriptional regulation and the N-end rule for protein degradation; and several of these enzymes have altered function on cancers and neurodegenerative disorders. Taken together, the vast majority of the human proteome is acetylated in a functionally important manner and alterations occur in human diseases. This suggests that protein acetylation may rival protein phosphorylation as a biologically important protein modification and that KATs and NATs represent important therapeutic targets.

  • Liszzczak, G., Arnesen, T. and Marmorstein, R. Structure of a Ternary Naa50p (NAT5/SAN) Nα-Terminal acetyltransferase complex reveals the molecular basis for substrate specific acetylation. (2011) Biol. Chem. 286:37002-37010. PMID: 21900231 URL: http://dx.doi.org/10.1074/jbc.M111.282863
  • Friedmann, D. R., Aguilar, A., Fan, J., Nachury, M. V. and Marmortein, R. Structure of the a-tubulin acetyltransferase, aTAT1, and implications for tubulin-specific acetylation. (2012) Natl. Acad. Sci. USA, 109:19655-19660. PMID: 23071314 URL: http://dx.doi.org/10.1073/pnas.1209357109
  • Cohen, T. J., Friedmann, D., Hwang, A.W. Marmorstein, R., and Lee, V. M. Y. The microtubule-associated tau protein has intrinsic acetyltransferase activity. (2013)Nature Struc. Mol. Biol.20:756-762. PMID: 23624859. URL: http://dx.doi.org/10.1038/nsmb.2555
  • Liszczak, G., Goldberg, J. M., Foyn, H., Petersson, E. J., Arnesen, T. and Marmorstein, R. Molecular basis for amino-terminal acetylation by the heterodimeric NatA complex. (2013) Struc. Mol. Biol.20:1098-1105. PMID: 23912279 URL: http://dx.doi.org/10.1038/nsmb.2636

My laboratory has pioneered molecular studies on the Sirtuin proteins. Sirtuin enzymes are NAD+-dependent histone and protein deactylases and/or ADP-ribotransferases that have been implicated in the regulation of gene expression, cellular aging, adipogenesis, type II diabetes and several neurodegenerative disorders. We have determined the structure of these enzymes in several liganded forms and have developed novel small molecule sirtuin inhibitors. Together with associated biochemical studies, these studies have provided insights into the mode of catalysis and substrate-specific recognition by this protein family and have illuminated new avenues for small molecule effector design.

  • Zhao, K., Xiaomei, C., Clements, A. and Marmorstein, R. Structure and autoregulation of a yeast Hst2 homolog of Sir2. (2003)Nature Structural Biology 10:864-871. PMID: 14502267
  • Zhao, K., Harshaw, R. Chai, X. and Marmorstein, R. Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD+-dependent Sir2 histone/protein deacetylases. (2004) Natl. Acad. Sci. USA101:8563-8568. PMID: 1510415; PMCID: PMC423234
  • Sanders, B. D., Jackson, B., Brent, M., Taylor, A. M., Dang, W., Berger. S. L., Schreiber, S. L., Howitz. K and Marmorstein, R. Identification and characterization of novel sirtuin inhibitor scaffolds. (2009)Bioorganic Medicinal Chem. 17:7031-7041. PMID: 19734050; PMCID: PMC2929362.  URL: http://dx.doi.org/10.1016/j.bmc.2009.07.07.
  • Pan, M., Yuan, H., Brent, M., Ding, E. C. and Marmorstein, R. SIRT1 contains N- and C-terminal regions that potentiate deactylase activity. (2012) Biol. Chem. 287:2468-2476. PMID: 22157016.  URL: http://dx.doi.org/10.1074/jbc.M111.285031

My laboratory has leveraged out expertise in biochemistry and X-ray crystallography with small molecule screening for the structure-based Inhibitor development for therapy of melanoma and other cancers. There is a particular interest in melanoma and the laboratory had developed inhibitors to several important oncogenic kinases in melanoma including BRAF, PI3K, PAK1 and S6K1. The laboratory has also targeted the oncoproteins E7 and E6 from human papillomavirus (HPV).  HPV is known to be the causative agent of a number of epithelial cancers, most notably cervical cancer, and has also been implicated to have a causative role in about 20% of head and neck cancers as well as several other cancers.  We have recently reported on the development of potent and selective HPV-E7 and HPV-E6 inhibitors.  These studies have important implications for therapy.

  • Xie, P., Williams, D. S., Atilla-Gokcumen, G. E., Milk, L., Xiao, M., Smalley, K. S. M., Herlyn, M., Meggers, E., and Marmorstein, R. Structure-based design of an organoruthenium Phosphatidyl-Inositol-3-Kinase inhibitor reveals a switch governing lipid kinase potency and selectivity. (2008)ACS Chem. Biol. 3:305-316. PMID: 18484710 URL: http://dx.doi.org/10.1021/cb800039y
  • Qin, J., Xie, P., Ventocila, C., Zhou, G., Vultur, A., Chen, Q., Lu, Q., Herlyn, M., Winkler, J. and Marmorstein, R. Identification of a novel family of BRAFV600E (2012) J. Med. Chem.55:5220-5230. PMID: 22537109 URL: http://dx.doi.org/10.1021/jm3004416
  • Fera, D., Schultz, D. C. Hodawadekar, S., Reichman, M., Donover, P. S., Melvin J., Troutman, S., Kissil, J., Huryn, D. M. and Marmorstein, R. Identification and characterization of small molecule antagonists of pRb inactivation by viral oncoproteins. (2012)Chemistry & Biology, 19:518-528. PMID: 22520758.  URL: http://dx.doi.org/10.1016/j.chembiol.2012.03.007
  • Malecka, K.A., Fera, D., Schultz, D.C., Hodawadekar, S., Reichman, M., Donover, P.S., Murphy, M.E. and Marmorstein, R. Identification and characterization of small molecule human papillomavirus E6 inhibitors. (2014)ACS Chem. Biol. 9:1603-1612. PMID: 24819397; PMCID: PMC4045318 . URL: http://dx.doi.org/10.1021/cb500229d