Cynthia Wolberger

Cynthia Wolberger

Professor, Department of Biophysics and Biophysical Chemistry, School of Medicine

714 WBSB
Office: 410-955-0728 | Lab: 410-955-3967
cwolberg@jhmi.edu
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Biography
Research
Publications

Cynthia Wolberger studied physics as an undergraduate at Cornell University and received her PhD in Biophysics from Harvard University, where she determined the x-ray crystal structure of a phage repressor-DNA complex with Steve Harrison and Mark Ptashne. After postdoctoral studies at UCSF and Johns Hopkins, where she worked on the structural basis of homeodomain-DNA recognition, Wolberger joined the Johns Hopkins School of Medicine faculty in 1991. During her time at Hopkins, Wolberger has studied the structural basis for combinatorial regulation of gene expression, the molecular mechanisms of the sirtuin family of protein deacetylases and, most recently, ubiquitin signaling. A current focus of the lab is on mechanisms by which ubiquitin plays a signaling role in transcription and in the DNA damage response.

The attachment of the small protein, ubiquitin, to lysine residues serves a wide 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. We are also studying cross-talk between multiple types of histone modifications including ubiquitination and acetylation.

Morgan MT, Haj-Yahya M, Ringel AE, Bandi P, Brik A, Wolberger C (2016) Structural basis for histone H2B deubiquitination by the SAGA DUB module. Science 351:725-8.

Ringel AE, Cieniewicz AM, Taverna SD, Wolberger C. (2015) Nucleosome competition reveals processive acetylation by the SAGA HAT module. Proc Nat Acad Sci USA, 112:E5461-70.

Wiener, W., A.T. DiBello, P.M. Lombardi, C.M. Guzzo, X. Zhang, M.J. Matunis, and C. Wolberger. (2013) E2 ubiquitin conjugating enzymes regulate the deubiquitinating activity of OTUB1. Nature Structural and Molecular Biology 20:1033-9.

Berndsen, C.E., R. Wiener, I.W. Yu, A.E. Ringel, and C. Wolberger. (2013) A conserved asparaginer has a structural role in ubiquitin-conjugating enzymes. Nat. Chem. Biol. 9:154-156.

Wiener, R., X. Zhang, T. Wang, and C. Wolberger. (2012) The mechanism of OTUB1-mediated inhibition of ubiquitination. Nature 483:618-622.

Samara, N.L., A.B. Datta, C.E. Berndsen, X. Zhang, T. Yao, R.E. Cohen, and C. Wolberger. (2010) Structural insights into the assembly and function of the SAGA deubiquitinating module. Science 328:1025-1029.

Complete list of published work on Pubmed MyBibliography