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
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, X-ray crystallographic and cryo-EM 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, Oncoproteins, X-ray Crystallography, Cryo-EM, Enzymology, Structure, Biophysics, Inhibitor development.

Description of Research
The Marmorstein laboratory studies the molecular mechanisms of protein post- and co-translational modification with a particular focus on protein acetylation and phosphorylation and chromatin regulation. The laboratory uses a broad range of molecular, biochemical and biophysical research tools centered on macromolecular structure determination using X-ray crystallography and cryo-electron microscopy. 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, and the use of high-throughput small molecule screening and structure-based design strategies towards the development of protein-specific small-molecule probes to be used to further interrogate protein function and for development into therapeutic agents. Specific areas of focus are described below:

Epigenetic regulation
DNA within the eukaryotic nucleus is compacted into chromatin containing histone proteins and its appropriate regulation orchestrates gene expression programs that allow cells with identical genetic information to exhibit different phenotypes. These epigenetic changes are mediated by proteins that recognize DNA and native and modified histones; assemble chromatin called histone chaperones; modify the histones through the addition or removal of functional chemical groups such as acetyl, methyl or phosphate; and non-coding RNA molecules. The laboratory is particularly interested in understanding the molecular mechanism of DNA binding proteins, histone chaperones and histone post-translational modifications enzymes. The laboratory is also studying the molecular links between metabolism and epigenetic regulation.

Protein acetyltransferases
Thousands of proteins, including 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 broad family of protein acetyltransferases that acetylate lysine side chains (KATs), protein N-termini (NATs) and other substrates. The laboratory is particularly interested in how these enzymes are regulated by protein cofactors to modulate substrate activity and specificity, and how protein acetyltransferases might be targeted by small molecule compounds to create molecular probes and therapeutic compounds. The laboratory is also studying the molecular mechanism of metabolism of the protein acetyltransferase cofactor, acetyl-CoA.

Cancer Biology
The laboratory is studying the structure and function of proteins that promote cancer (oncoproteins) and proteins that suppress cancer (tumor suppressors) with a goal of understanding molecular mechanism and developing 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 MAP kinase signaling pathway.

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:
Austin Vogt
Dan Ricketts
Xuepeng Wei
Andrea Acevedo

Predoctoral Students:
Sunbin Deng
Elaine Zhou
Mary Szurgot
Kollin Schultz
Meng Li

Lab Manager
Shirley Zeng

Selected Publications

Cheng, H., Gottlieb, L., Marchi, E., Kleyner, R., Bhardwaj, P., Rope, A.F., Rosenheck,S. Mutton, S., Philippe, C., Eyaid, W., Alkuraya, F., Toribio, J., Mena, R., Prada, C.E., Stessman, H., Bernier, R., Wermuth, M., Kauffmann, B., Blaumeiser, B., Kooy, R.F., Baralle, D., Mancini, G.M.S., Conway, S.J., Xia, F., Chen, Z., Meng, L., Mihajlovic, L., Marmorstein, R. and Lyon, G.J. : Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15. Human Molecular Genetics 28: 2900-2919, February 2020.

Deng, S., McTiernan, N., Wei, X., Arnesen, T. and Marmorstein, R. : Molecular basis for N-terminal acetylation by human NatE and its modulation by HYPK. Nature Comm. 11: 14584-14587, February 2020.

Song, S., Perez, J.V., Svitko, W., Ricketts, M.D., Dean, E., Schultz, D., Marmorstein, R. and Johnson, F.B. : Rap1-mediated nucleosome displacement can regulate gene expression in senescent cells without impacting the pace of senescence Aging Cell 19: e13061, January 2020.

Wei, X., Schultz, K., Bazilevsky, G.A., Vogt, A. and Marmorstein R: Molecular basis of acetyl-CoA production by ATP-citrate lyase. Nature Structural & Molecular Biology 27: 33-41, January 2020.

Deng, S., Magin, R.S., Wei, X., Pan, B., Petersson, E.J. and Marmorstein, R.: Structure and mechanism of acetylation by the N-terminal dual enzyme NatA/Naa50 complex. Structure 27: 1057-1070, July 2019.

Ricketts, M.D., Dasgupta, N., Fan, J., Han, J., Gerace, M., Tang, Y., Black, B.E., Adams, P.D. and Marmorstein, R. : The HIRA histone chaperone complex subunit UBN1 harbors H3/H4 and DNA binding activity. J. Biol. Chem. 294: 9239-9259, June 2019.

Bazilevsky, G.A., Affronti, H.C., Wei, X., Campbell, S.L., Wellen, K.E. and Marmorstein. R. : ATP-citrate lyase multimerization is required for coenzyme-A substrate binding and catalysis. J. Biol. Chem. 294: 7529-7268, May 2019.

Rebecca, V.W., Nicastri, M.C., Fennelly, C., Chude, C.I., Barber-Rotenberg, J.S., Ronghe, A., McAfee, Q., McLaughlin, N.P., Zhang, G., Goldman, A.R. Ojha, R., Paiao, S., Noguera-Ortega, E., Martorella, A., Alicea, G.M. Lee, J.J., Schucter. L.M., Xu,. X. Herlyn, M., Marmorstein, Gimotty, P.A., Speicher, D.W., Winkler, J.D., Amaravadi, R.K. : PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. Cancer Discovery 9: 220-229, February 2019.

Ricketts, M.D, Han, J., Szurgot, M. and Marmorstein, R.: Molecular basis for chromatin assembly and modification by multi-protein complexes. Protein Science 28: 329-343, 2019.

Gottlieb, L. and Marmorstein, R. : Biochemical and structural analysis of N-terminal acetyltransferases. Methods Enzymol. 626: 271-299, 2019.

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Last updated: 05/19/2020
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