- B.S. University of California at Davis (1984)
- M.S. University of Chicago (1989)
- Ph.D. University of Chicago (1989)
- Postdoctoral Fellow, Harvard University (1989-1994)
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:
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.
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.
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.
Complete bibliography is available at: http://www.ncbi.nlm.nih.gov/pubmed/?term=Marmorstein+R