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Cynthia Wolberger
Professor, Johns Hopkins University School of Medicine
Investigator, Howard Hughes Medical Institute
725 N. Wolfe St., 714 WBSB
Baltimore, MD 21205

Phone: 410-955-0728
Lab: 410-955-3967
Email: cwolberg@jhmi.edu

Lab Website:

http://biophysics.med.jhmi.edu/wolberger/

Assistant: Kathie Kolish
 

Short Research Description:
Mechanisms of transcription regulation and ubiquitin signaling.

Research Interests:
The attachment of the small protein, ubiquitin, to lysine residues serves a remarkable variety of signaling functions. In addition to its best-known role in targeting proteins for proteasomal degradation, ubiquitination also plays a non-degradative role in transcriptional regulation, DNA damage repair, and the inflammatory response. Ubiquitin is attached to substrates in a cascade of enzymatic reactions involving three separate enzymes, E1, E2 and E3. The resulting 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. Monoubiquitination, in turn, places a key role in transcription activation and elongation, as well as intracellular trafficking. We study the structural basis for both the assembly and disassembly of linkage-specific polyubiquitin chains, as well the removal of monoubiquitin from histone substrates. A current focus is on ubiquitination events centered on chromatin, which regulate transcription and the response to DNA damage.

CW
Acetylation of lysine residues plays a regulatory role in many processes, most notably in the regulation of mRNA transcription. We are studying coactivators complexes that acetylate histones as well as NAD+-dependent deacetylases known as sirtuins. We use a combination of crystallography and biochemical analysis to study the enzymatic mechanism of these enzymes and how it is regulated by inhibitors and metabolites.
 
Selected Publications:
 

Wiener R, DiBello AT, Lombardi PM, Guzzo CM, Zhang X, Matunis MJ, Wolberger C. E2 ubiquitin-conjugating enzymes regulate the deubiquitinating activity of OTUB1 (2013) Nat Struct Mol Biol. 20:1033-9.

Berndsen CE, Wiener R, Yu IW, Ringel AE, Wolberger C.(2013) A conserved asparagine plays a structural role in ubiquitin-conjugating enzymes. Nature Chemical Biology 9:154-6.

Wiener R, Zhang X, Wang T, Wolberger C. (2012) The mechanism of OTUB1-mediated inhibition of ubiquitination. Nature 483: 618-22.

Samara NL, Ringel AE, Wolberger C (2012) A Role for Intersubunit Interactions in Maintaining SAGA Deubiquitinating Module Structure and Activity. Structure 20:1414-24

Bheda P, Swatkoski S, Fiedler KL, Boeke JD, Cotter RJ, Wolberger C. (2012) Biotinylation of lysine method identifies acetylated histone H3 lysine 79 in Saccharomyces cerevisiae as a substrate for Sir2. Proc Natl Acad Sci U S A. 109: E916-25.

Samara, NL, Datta AB, Berndsen CE, Zhang X, Yao T, Cohen RE, and Wolberger C (2010) Structural insights into the assembly and function of the SAGA deubiquitinating module. Science 328:1025-1029.

Hawse, W.F., K.G. Hoff, D. Fatkins, A. Daines, O.V. Zubkova, V.L. Schramm, W. Zheng, and C. Wolberger (2008) Structural insights into intermediate steps in the Sir2 deacetylation reaction. Structure 16:1368-1377.

Eddins, M.J., C.M. Carlile, K.M. Gomez, C.M. Pickart, and C. Wolberger. (2006) Mms2/Ubc13 covalently bound to ubiquitin: structural basis of linkage-specific polyubiquitin chain formation. Nat. Struct. Mol. Biol. 13:915-920.

 
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