Ronen Marmorstein, Ph.D.

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Professor of Biochemistry and Biophysics
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.
M.S. (Physical Chemistry )
University of Chicago, 1989.
Ph.D. (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 for 2006-2007
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
Julie Barber-Rotenberg
John Domsic
Allison Haigney
Jasna Maksimoska
Adam Olia
Yadilette Rivera-Colon
Pingfeng Zhang

Predoctoral Students
Gleb Bazilevsky
Michael Grasso
Joe Han
Robert Magin
Cheryl Mccullough
Dan Ricketts

Visiting Scientist
Svein Stove

Lab Manager
Emily Mattes

Selected Publications

Plasschaert, R., Vigneau, S., Tempera, I., Gupta, R., Maksimoska, J., Everett, L., Davuluri, R., Marmorstein, R., Lieberman, P., Schultz, D., Hannenhalli, S. and Bartolomei, M. : CTCF binding site sequence differences are associated with unique regulatory and functional trends during embryonic stem cell differentiation. Nuc. Acids Res. 2013 (in press).

Friedmann, D.R. and Marmorstein, R.: Structure and mechanism of non-histone protein acetyltransferase enzymes FEBS J. 2013 (in press).

Marmorstein, R. and Zhou, M-M. : Writers and readers of histone acetylation: Structure, Mechanism and Inhibition. Epigenetics Allis, C.D., Jenuwein, T. and Reinberg, D. (eds.). 2013 (in press).

Friedmann David R, Marmorstein Ronen: Structure and mechanism of non-histone protein acetyltransferase enzymes. The FEBS journal 280(22): 5570-81, Nov 2013.

Licciulli Silvia, Maksimoska Jasna, Zhou Chun, Troutman Scott, Kota Smitha, Liu Qin, Duron Sergio, Campbell David, Chernoff Jonathan, Field Jeffrey, Marmorstein Ronen, Kissil Joseph L: FRAX597, a Small Molecule Inhibitor of the p21-activated Kinases, Inhibits Tumorigenesis of Neurofibromatosis Type 2 (NF2)-associated Schwannomas. The Journal of biological chemistry 288(40): 29105-14, Oct 2013.

Domsic John F, Chen Horng-Shen, Lu Fang, Marmorstein Ronen, Lieberman Paul M: Molecular Basis for Oligomeric-DNA Binding and Episome Maintenance by KSHV LANA. PLoS pathogens 9(10): e1003672, Oct 2013.

Villanueva Jessie, Infante Jeffrey R, Krepler Clemens, Reyes-Uribe Patricia, Samanta Minu, Chen Hsin-Yi, Li Bin, Swoboda Rolf K, Wilson Melissa, Vultur Adina, Fukunaba-Kalabis Mizuho, Wubbenhorst Bradley, Chen Thomas Y, Liu Qin, Sproesser Katrin, Demarini Douglas J, Gilmer Tona M, Martin Anne-Marie, Marmorstein Ronen, Schultz David C, Speicher David W, Karakousis Giorgos C, Xu Wei, Amaravadi Ravi K, Xu Xiaowei, Schuchter Lynn M, Herlyn Meenhard, Nathanson Katherine L: Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma. Cell reports 4(6): 1090-9, Sep 2013.

Liszczak Glen, Goldberg Jacob M, Foyn Håvard, Petersson E James, Arnesen Thomas, Marmorstein Ronen: Molecular basis for N-terminal acetylation by the heterodimeric NatA complex. Nature structural & molecular biology 20(9): 1098-105, Sep 2013.

Liszczak Glen, Marmorstein Ronen: Implications for the evolution of eukaryotic amino-terminal acetyltransferase (NAT) enzymes from the structure of an archaeal ortholog. Proceedings of the National Academy of Sciences of the United States of America 110(36): 14652-7, Sep 2013.

Taylor Martin S, Ruch Travis R, Hsiao Po-Yuan, Hwang Yousang, Zhang Pingfeng, Dai Lixin, Huang Cheng Ran Lisa, Berndsen Christopher E, Kim Min-Sik, Pandey Akhilesh, Wolberger Cynthia, Marmorstein Ronen, Machamer Carolyn, Boeke Jef D, Cole Philip A: Architectural Organization of the Metabolic Regulatory Enzyme Ghrelin-O-Acyltransferase. The Journal of biological chemistry Sep 2013.

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Last updated: 02/11/2015
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