Ronen Marmorstein, Ph.D.

faculty photo
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
Education:
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
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
Dan Ricketts
Xuepeng Wei
Andrea Acevedo

Predoctoral Students:
Joe Han
Gleb Bazilevsky
Leah Gottlieb
Sunbin Deng
Elaine Zhou
Mary Szurgot

Lab Manager
Shirley Zeng

Selected Publications

Goris, M., Magin, R.S., Foyn, H., Myklebust, L.M., Varland, S., Ree, R., Drazic, A., Bhambra, P. Støve, S.I., Baumann, M., Haug, B.E., *Marmorstein, R., *Arnesen, T. : Structural determinants and cellular environment define processed actin as the sole substrate of the N-terminal acetyltransferase Naa80. Proc. Natl. Acad. Sci. April 2018.

Mawhinney, M.T., Liu, R., Lu, F., Maksimoska, J., Damico, K., Marmorstein, R., Lieberman, P.M. and Urbanc, B. : CTCF-Induced circular DNA complexes observed by atomic force microscopy. J. Mol. Biol. 430, March 2018.

Grasso, M., Estrada, M.A., Berrios, K.N., Winkler, J.D. and Marmorstein R. : N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK632) promotes inhibition of BRAF through the induction of inhibited dimers. J. Med. Chem 2018.

Arnesen, T., Marmorstein, R. and Dominquez, R.: Actin’s N-terminal acetyltransferase uncovered. Cytoskeleton 2018.

Gottlieb, L. and Marmorstein, R. : Structure of human NatA and its regulation by the Huntingtin interacting protein HYPK. Structure 2018.

Cope, N., Candelora, C., Wong, K., Kumar, S., Nan, H., Grasso, M., Novak, B., Li, Y., Marmorstein, R., Wang, Z. : Mechanism of BRAF activation through biochemical characterization of teh recombinant full-length protein. Chembiochem 2018.

Ray-Gallet, D., Ricketts, M.D., Sato, Y., Gupta, K., Boyarchuk, E., Senda, T., Marmorstein, R., and Almouzni, G.: Functional activity of the H3.3 histone chaperone complex HIRA requires trimerization of the HIRA subunit. Nat. Commun. 2018.

Emptage, R.P., Lemmon, M.A., Ferguson, K.M. and Marmorstein R: Structural basis for MARK1 kinase autoinhibition by its KA1 domain. Structure 2018.

Michaelides, M.R., Kluge A., Patane, M., Van Drie, J.H., Wang, C., Hansen, T.M., Risi, R.M., Mantei, R., Hertel, C., Karkurichi, K., Nesterov, A., McElligott, D., de Vries, P., Langston, J.W., Cole, P.A., Marmorstein, R., Liu, H., Lasko, L., Broomberg, K.D., Lai, A., and Kesicki, E.A. : Discovery of Spiro Oxazolidinediones as selective, orally bioavailable inhibitors of p300/CBP histone acetyltransferases. ACS Med. Chem. Lett. 9, December 2017.

Emtage, R.P., Schoeberger, M.J. Fergusion, K.M., and Marmorstein, R.: Intramolecular autoinhibition of Checkpoint Kinase 1 is mediated by conserved basic motifs of the C-terminal Kinase Associated-1 domain. J. Biol. Chem. 292: 19024-19033, Novmber 2017.

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Last updated: 09/12/2018
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