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Ronen Marmorstein, Ph.D.

Ronen Marmorstein

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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.
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
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

Magin, R.S., March, Z.M. and Marmorstein, R.: The N-terminal Acetyltransferase Naa10/ARD1 Does Not Acetylate Lysine Residues. J. Biol. Chem. 291: 5270-5277, March 2016.

Haigney, A., Ricketts, M. D. and Marmorstein, R.: Dissecting the Molecular Roles of Histone Chaperones in Histone Acetylation by Type B Histone Acetyltransferases (HAT-B). J. Biol. Chem. 290: 30648-30657, December 2015.

Dou, Z., Xu, C., Donahue, G., Shimi, T., Pan, J. A., Zhu, J., Ivanov,A., Capell, B. C., Drak, A. M., Shah, P. P., Catanzaro, J. M., Ricketts, M. D., Lamark, T., Adam, S. A., Marmorstein, R., Zong, W. X., Johansen, T., Goldman, R. D., Adams, P. D., and Berger, S. L. : Autophagy mediates degradation of nuclear lamina. Nature 527: 105-109, November 2015.

Ndubaku, C. O., Crawford, J. J., Drobnick, J., Allagas, I., Campbell, D., Dong, P., Dornan, L. M., Duron, S., Epler, J., Gazzard, Heise, C. E., Hoeflich, K. P., Jakubiak, D., La, H., Lee, W., Lin, B., Lyssikatos, J. P., Maksimoska, J., Mormorstein, R., Murray, L. J., O’Brien, T., Oh, A., Ramaswamy, S., Wang, W., Zhao, X., Zhong, Y., Blackwood, E., and Rudolph, J.: Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pK a Polar Moiety. ACS Med. Chem. Lett. 6: 1241-1246, October 2015.

Olia, A.S., Barker, K., McCollough, C.E., Tang, H.Y., Speicher, D.W., Qui, J., LaBaer, J. and Marmorstein, R. : Nonenzymatic Protein Acetylation Detected by NAPPA Protein Arrays. ACS Chemical Biol. 10: 2034-2047, September 2015.

Ricketts, M.D., Frederick, B., Hoff. H., Tang, Y., Schultz, D.C. Rai, T.S., Vizioli, M.G. Adams, P.D. and Marmorstein, R. : Ubinuclein-1 confers histone H3.3-specific-binding by the HIRA histone chaperone complex. Nature Communications 6: 7711, July 2015.

Myklebust, L.M., Van Damme, P., Støve, S.I., Abboud, A., Kalvik, T.V., Dörfel, M., Grauffel, C., Jonckheere, V., Wu, Y., Kaasa, H., Liszczak, G., Marmorstein, R., Reuter, N., Lyon, G.J., Gevaert, K. and Arnesen, T. : Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects. Human Mol. Genet. 24: 1956-1976, April 2015.

Magin, R.S., Liszczak, G.P. and Marmorstein, R. : The molecular basis for histone H4- and H2A-specific amino-terminal acetylation by NatD. Structure 23: 332-341, February 2015.

Qin, J., Rajaratnam, R., Feng, L., Salami, J., Barber-Rotenberg, J.S., Domsic, J., Reyes-Uribe, P., Liu, H., Dang, W., Berger, S.L., Villanueva, J., Meggers, E. and Marmorstein, R.: Development of organometallic S6K1 inhibitors. J. Med. Chem. 58: 305-314, January 2015.

Tsai K., Chan L., Conn K., Dheekollu J., Lai F., Domsic J., Marmorstein R., Shiekhattar R., Schang L., and Lieberman P.: Viral reprogramming of the Daxx-Histone H3.3 chaperone during EBV pre-latent infection. J. Virol. 88: 14350-14363, Dec 2014.

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Last updated: 08/23/2016
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