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Wolberger Research Lab spacer Johns Hopkins University Howard Hughes Medical Institute
CW Lab1 CW Lab2

CYNTHIA WOLBERGER

Post-translational modification of lysine residues plays a central role in numerous biological processes. Our research centers on two examples of lysine modification: the Sir2 class of NAD+-dependent deacetylases and the assembly and recognition of linkage-specific polyubiquitin chains. We use x-ray crystallography, together with biochemical, biophysical and genetic analysis, to gain insight into the enzymatic mechanisms and protein-protein interactions underlying these processes.

Acetylation of lysine residues plays a regulatory role in many processes, most notably in the regulation of mRNA transcription. The Sir2 enzymes, known as sirtuins, are NAD+-dependent deacetylases that regulate numerous processes such as transcriptional silencing in yeast, lifespan regulation, fat mobilization, and enzyme activity. We use a combination of crystallographic and biochemical analysis to study the enzymatic mechanism of sirtuins and how they are regulated by inhibitors and metabolites. Some sirtuins also catalyze a related reaction known as ADP ribosylation, and we are exploring the basis for the switch between these two reactions. We are also studying how yeast Sir2 is recruited to telomeres as part of a complex that includes Rap1.

The attachment of the small protein, ubiquitin, to lysine residues serves a variety of signaling functions. The ubiquitin modification can consist of a single ubiquitin or a polyubiquitin chain in which the C-terminus of one ubiquitin is covalently linked to one of seven lysine residues on the next. The particular linkage type determines biological function: K48-linked polyubiquitin chains target proteins for destruction by the proteasome, whereas K63-linked chains play a non-degradative role in DNA damage tolerance and NF-kB activation. We study the structural basis for both the assembly and disassembly of linkage-specific polyubiquitin chains, as well as the way in which particular chain topologies are recognized in the cell.


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Last updated: November 5, 2009.