Ronen Marmorstein, Ph.D.

Ronen Marmorstein, Ph.D.

George W. Raiziss Professor and Vice-Chair, Department of Biochemistry and Biophysics Investigator, Abramson Family Cancer Research Institute

Contact Information

The Perelman School of Medicine at the University of Pennsylvania
Department of Biochemistry and Biophysics
454 BRB II/III
421 Curie Blvd, Philadelphia, PA 19104-6161
Office: 215-898-7740
Fax: 215-746-5511
marmor@upenn.edu

Research Interest

The Marmorstein laboratory studies the molecular mechanisms of (1) epigenetic regulation (2) protein post- and co-translational modification with a particular focus on protein acetylation, and (3) enzyme signaling in cancer and metabolism.  The laboratory uses a broad range of biochemical, biophysical and structural research tools (X-ray crystallography and cryo-EM) to determine macromolecular structure and mechanism of action.  The laboratory also uses high-throughput small molecule screening and structure-based design strategies to develop protein-specific small-molecule probes to interrogate protein function and for preclinical studies.

Contribution To Science

My laboratory has pioneered the structure-function analysis of histone acetyltransferases (HATs) and continues to make seminal contributions in this area.  Specifically, my laboratory determined the first crystal structure of a type A HAT and characterized its mechanism of catalysis, and the first to describe the mode of histone substrate binding by a HAT. My laboratory has extended our studies to the broader family of N- acetlyltransferases including the non-histone lysine acetyltrasnferases (KATs) and the N-amino acetyltransferases (NATs).  We have uncovered important molecular signatures that distinguish HATs, KATs and NATs. My laboratory has also contributed to the development of acetyltransferase inhibitors. The vast majority of the human proteome is acetylated in a functionally important manner and alterations occur in human diseases.  This suggests that protein acetylation may rival protein phosphorylation as a biologically important protein modification and that KATs and NATs represent important therapeutic targets.

  • Lasko, L.M., Jakob, C.G., Edalji, R.P., Qiu W., Montgomery D., Digiammarino .EL., 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 SH, Michaelides M.R., Lai A., Bromberg K.D. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. (2017) Nature, 550:128-132. PMID:28953875; PMCID:PMC6050590
  • Gottlieb, L. and Marmorstein, R. Structure of human NatA and its regulation by the Huntingtin interacting protein HYPK. (2018) Structure 26:925-935. PMID: 29754825: PMCID: PMC6031454
  • 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. (2019) Structure, 27: 1057-1070. PMID:31155310; PMCID:6610660
  • 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, (2020) Nature Comm., 11: 14584-14587. PMID32042062: PMCID: PMC7010799

My laboratory is studying the molecular basis for how chromatin is assembled and maintain by histone chaperone complexes.  We have focused on the binding and histone deposition of H3/H4 complexes by the ASF1 and VPS75 proteins and the multisubunit HIRA complex, which specifically deposits the histone H3 variant, H3.3, in a replication independent manner.  Histone H3.3 is deposited at active genes, after DNA repair and in certain forms of heterochromatin in non-proliferating senescent cells, and recurrent H3.3 mutations are found in pediatric glioblastoma and misregulation of H3.3-specific activities in tumor growth and leukemia exemplifies the necessity for proper regulation of H3.3-specific deposition pathways. Together with the Peter Adams laboratory we have pioneered a molecular understanding of the HIRA complex highlighting the particular importance of the HIRA and Ubn1 subunits of H3.3-specific activities.

  • 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 specificity by the HIRA histone chaperone complex. (2015) Nature Communications. 6:7711-. PMID: 26159857: PMCID: PMC4509171
  • 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), (2015) J. Biol. Chem., 290:30648-30657. PMID: 26522166: PMCID: PMC4683284
  • 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. (2018) Nat. Commun. 9:3103. PMID:30082790: PMCID: PMC6078998
  • 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. (2019) J. Biol. Chem., 294: 9239-9259. PMID:31040182; PMCID: PMC6556585

My laboratory has leveraged our expertise in biochemistry and X-ray crystallography with small molecule screening for structure-based Inhibitor development for therapy of melanoma and other cancers.  There is a particular interest in melanoma and the laboratory had developed inhibitors to several important oncogenic kinases in melanoma including BRAF, PI3K, PAK1 and S6K1. The laboratory has also targeted the oncoproteins E7 and E6 from human papillomavirus (HPV), the causative agent of a number of epithelial cancers, and a significant portion of head and neck cancers. These studies have important implications for therapy.

  • 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. (2015) J. Med. Chem. 58:305-314. PMID: 25356520; PMCID: PMC4289024
  • 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. (2016) ACS Chem. Biol. 11: 2876-2888. PMID: 27571413: PMCID: PMC5108658
  • 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. (2017) J. Biol. Chem. 292:19024-19033. PMID:28972186: PMCID: PMC5704483
  • Grasso, M., Estrada, M.A., Berrios, K.N., Winkler, J.D. and Marmorstein, R. N-(7-Cyano-6-(4-fluro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK632) promotes inhibition of BRAF through the induction of inhibited dimers. (2018) J. Med. Chem. 61:5034-5046. PMID: 29727562: PMCID: PMC6540792

My laboratory has more recently studied the connection between metabolism with cancer signaling and chromatin regulation, with a particular focus on the acetyl-CoA metabolism and metabolite acylation enzymes such as ATP citrate lyase (ACLY). Our studies uncovered the molecular mechanism of ACLY and provided a molecular scaffold for the structure-based development of ACLY inhibitors for therapy of cancer and metabolic and cardiovascular disorders.

  • 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, (2019) J. Biol. Chem. 294:7529-7268. PMID: 30877197; PMCID: PMC6509486
  • Wei, X., Schultz, K., Bazilevsky, G.A., Vogt, A. and Marmorstein R. Molecular basis of acetyl-CoA production by ATP-citrate lyase. (2020) Nature Structural & Molecular Biology 27:33-41. PMID: 31873304

Lab Members

FIRST NAME:LAST NAME:TITLE:EMAIL:
RonenMarmorsteinPImarmor@upenn.edu
ReneeBarbosaUndergraduate Student reneeb22@sas.upenn.edu
SunbinDengGraduate Studentsunbin@sas.upenn.edu
SarahGardnerGraduate Studentsgardne@pennmedicine.upenn.edu
MengLiGraduate studentmeng1@sas.upenn.edu
DanRickettsPostdoctoral Fellowmicric@mail.med.upenn.edu
KollinSchultzGraduate Studentkollin.schultz@pennmedicine.upenn.edu
JulianaSuppleeGraduate Studentsuju@pennmedicine.upenn.edu
MarySzurgotGrad Studentmszurgot@pennmedicine.upenn.edu
AustinVogtPostdoctoral Fellowadvogt@gmail.com
XuepengWeiPostdoctoral FellowXuepeng.Wei@pennmedicine.upenn.edu
ShirleyZengResearch Technicianshirley.zeng@pennmedicine.upenn.edu
ElaineZhouGraduate Studentohelaine@sas.upenn.edu