Short Research Description:

Mechanisms of transcription regulation, structural basis of 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.

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.

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.