Ronen Marmorstein, Ph.D.

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George W. Raiziss Professor
Department: Biochemistry and Biophysics

Contact information
BRB II/III, Room 454
421 Curie Blvd.
Philadelphia, PA 19104-6161
Office: (215) 898-7740
Fax: (215) 746-5511
B.S. (Chemistry and Genetics)
University of California, Davis, 1984.
Ph.D. (Chemistry)
University of Chicago, 1989.
M.S. (Physical Chemistry )
University of Chicago, 1989.
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Description of Research Expertise

Research Interests
Biochemical, biophysical and X-ray crystallographic techniques are employed to study the posttranslational modification of histones and other proteins and the misregulation of such modifications in cancer and metabolic disorders.

Key words: Epigenetics, Transcription, Chromatin regulation, Protein-DNA recognition, Posttranslational modification, Tumor Suppressors, Viral oncoproteins, X-ray Crystallography, Enzymology, Structure, Biophysics, Inhibitor development.

Description of Research
The laboratory is using a broad range of molecular, biochemical and biophysical research tools centered on 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 of therapeutic agents.

Chromatin recognition, assembly and histone modifications
DNA within the eukaryotic nucleus is compacted into chromatin containing histone proteins and its appropriate regulation orchestrates all DNA-templated reactions such as DNA transcription, replication and repair. Among the many proteins that regulate chromatin, the proteins that recognize DNA, assemble chromatin, called histone chaperones, and that modify the histones through the addition or removal of functional groups such as acetyl, methyl or phosphate play important roles. The laboratory is particularly interested in DNA binding proteins that mediate genomic stability such as p53 and FoxO; the histone chaperones HIRA, Asf1, Vps75 and their associated factors; and the family of histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes.

We are particularly interested in how DNA binding proteins navigate the recognition of their cognate DNA targets, how histone chaperones coordinate the assembly of distinct chromatin complexes correlated with different DNA regulatory processes, and how histone modification enzymes link catalysis to their substrate specific activities for their respective biological activities. More recently, we have been studying how the binding of accessory and regulatory protein subunits regulates the various activities of these proteins and in some cases we are developing small molecule protein specific inhibitors.

Protein acetyltransferases
Although much of the structural and biochemical studies on protein acetyltransferases from our laboratory and others have focused on histone acetyltransferases (HATs), recent proteomics studies have revealed that thousands of proteins, beyond histones, are acetylated throughout the cell to regulate diverse biological processes, thus placing acetyltransferases on the same playing field as kinases. Indeed, emerging biochemical and structural data further supports mechanistic and biological links between the two enzyme families. Because of this correlation, the laboratory is studying the broader family of protein acetyltransferase to address how they may differ from histone acetyltransferases, how they are regulated by autoacetylation and cofactors and how they might be targeted by small molecule compounds to create molecular probes and therapeutic compounds. To date, the laboratory has reported studies on the N-amino acetyltransferases and α-tubulin acetyltransferases and is studying other acetyltransferase enzymes.

Tumor Suppressors and oncoproteins
The laboratory is studying the structure and function of human and viral oncoproteins with a goal to develop small molecule inhibitors as molecular probes and as lead molecules for development to treat various cancers. There is a particular interest in melanoma and the laboratory had developed inhibitors to several important oncoprotein targets in melanoma including BRAF, PI3K and PAK1. The laboratory is also targeting 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 inhibitors, while the development of HPV-E6 inhibitors is in progress. The laboratory is also studying the structure and function of the tumor suppressor targets of HPV-E7 and –E6, pRb and p53, respectively.

Rotation Projects
Rotation Students with an interest in incorporating the techniques of molecular biology, biochemistry, X-ray crystallography, enzymology and inhibitor development to study areas of interest to the laboratory are encouraged to inquire by e-mail to Dr. Marmorstein to discuss specific rotation projects.

Lab personnel:
Postdoctoral Fellows:
Adam Olia
Julie Barber-Rottenberg
Austin Vogt
Ryan Emptage

Predoctoral Students:
Cheryl McCullough
Dan Ricketts
Joe Han
Michael Grasso
Gleb Bazilevsky
Robert Magin
Leah Gottlieb

Masters Student
Natalie Schribrowski

Postbac Student
Angel Payan

Lab Manager
Kevin D'Amico

Selected Publications

Simithy Johayra, Sidoli Simone, Yuan Zuo-Fei, Coradin Mariel, Bhanu Natarajan V, Marchione Dylan M, Klein Brianna J, Bazilevsky Gleb A, McCullough Cheryl E, Magin Robert S, Kutateladze Tatiana G, Snyder Nathaniel W, Marmorstein Ronen, Garcia Benjamin A: Characterization of histone acylations links chromatin modifications with metabolism. Nature communications 8(1): 1141, Oct 2017.

136. Lasko, L.M., Jakob, C.G., Edalji, R.P., Qiu W., Montgomery D., Digiammarino E.L., Hansen T.M., Risi R.M., Frey R, Manaves V., Shaw B., Algire M., Hessler P., Lam L.T., Uziel T., Faivre E., Ferguson D., Buchanan F.G., Martin R.L., Torrent M., Chiang G.G., Karukurichi K., Langston J.W., Weinert B.T., Choudhary C., de Vries P., Van Drie J.H., McElligott D., Kesicki E., Marmorstein R., Sun C., Cole P.A., Rosenberg S.H., Michaelides M.R., Lai A., Bromberg K.D. : Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature 550: 128-132, September 2017.

Feng, Z., Wang, L., Sun, Y., Xing, B., Jiang, Z., Domsic, J., Tian, J., Liu, X., Metz, D.C., Yang, X., Marmorstein, R., Ma, X. and Hua, X. : Menin and Daxx interact to control neuroendocrine tumors via epigenetic regulation of membrane metallo-endopeptidase. Cancer Research 77: 401-411, January 2017.

138. Magin, R.S., Deng, S., Zhang, H., Cooperman, B., and Marmorstein, R.: Probing the interaction between NatA and the ribosome for co-translational protein acetylation. PLoS One 12: e0186278, 2017.

Marmorstein, R. and Adams, P.A. : Epigenetic meets metabolism through PHB-mediated histone H3.3 deposition by HIRA. Stem Cell Inv. 4: 46-47, 2017.

139. Simithy, J., Sidoli, S., Yuan, Z.F., Coradin, M., Bhanu, N.V., Marchione, D.M., Klein, B.J., Bazilevsky, G.A., McCullough, C.E., Magin, R.S., Kutateladze, T.G., Snyder, N.W., Marmorstein, R. and Garcia, B. : Characterization of histone acylations link chromatin modifications with metabolism. Nature Communications 8: 1141, 2017.

Hwang, A.W. Trzeciakievicz, H., Friedmann, D., Yuan, C.X., Marmorstein, R., Lee, V.M. and Cohen, T.J. : Conserved Lysine Acetylation within the Microtubule-Binding Domain Regulates MAP2/Tau Family Members. PLoS One 11: e0168913, December 2016.

Rivera-Colón, Y., Maguire, A., Liszczak, G.P., Olia, A.S. and Marmorstein, R. : Molecular basis for cohesion acetylation by Establishment of Sister Chromatid Cohesion N-acetyltransferase ESCO1. J. Biol Chem. 291: 26468-26477, December 2016.

Grasso, M., Estrada, M.A., Ventocilla, C., Samanta, M., Maksimoska, J., Villanueva, J., Winkler, J.D. and Marmorstein, R. : Chemically linked vemurafenib inhibitors promote an inactive BRAFV600E conformation. ACS Chem. Biol. 11: 2876-2888, October 2016.

Rong, Z., Ouyang, Z., Magin, R.S., Marmorstein, R., Yu, H. : Opposing functions of the N-terminal acetyltransferases Naa50 and NatA in sister-chromatid cohesion. J. Biol. Chem. 291: 19079-19091, September 2016.

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Last updated: 01/24/2018
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