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Biophysics and Biophysical Chemistry
725 N. Wolfe Street
Baltimore MD 21205
Structural and molecular mechanisms of ubiquitin signaling and chromatin modification; regulation of transcription
Protein function is dynamically regulated in the cell by reversible posttranslational modifications. Lysine side chains are subject to a remarkably diverse array of modifications, ranging from acetylation to the attachment of polyubiquitin chains. Acetylation plays a central role in regulating transcription, whereas ubiquitination plays diverse roles, targeting substrates for degradation as well as non-degradative roles in a variety of signaling pathways. We use a combination of x-ray crystallography, solution biochemistry, cell-based assays, and a variety of biophysical tools to gain insights into the mechanisms underlying these essential cellular processes. A current focus is on ubiquitination events centered on chromatin, which regulate transcription and the response to DNA damage. 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. We study the mechanism by which mono- or polyubiquitin signals are attached to and removed from chromatin, as well as how histone ubiquitination regulates transcription and the DNA damage response. We are also interested in the mechanism of cross-talk between histone ubiquitination, acetylation and methylation, which together orchestrate the complex events underlying mRNA transcription and DNA repair.
Worden EJ, Hoffmann N, Wolberger C. (2019) Mechanism of cross-talk between H2B ubiquitination and H3 methylation by Dot1L. Cell, 176(6):1490-1501.
Nune M, Morgan MT, Connell Z, McCullough L, Jbara M, Sun H, Brik A, Formosa T, Wolberger C. (2019) FACT and Ubp10 collaborate to modulate H2B deubiquitination and nucleosome dynamics. eLife, pii: e40988. doi: 10.7554/eLife.40988
Morgan M, 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(6274):725-8.
Ringel AE, Cieniewicz AM, Taverna SD, Wolberger C (2015) Nucleosome competition reveals processive acetylation by the SAGA HAT module. Proc Natl Acad Sci U S A. 112(40):E5461-70.
Wiener W, DiBello AT, Lombardi PM, Guzzo CM, Zhang X, Maunis MJ, Wolberger C (2013) E2 ubiquitin conjugating enzymes regulate the deubiquitinating activity of OTUB1. Nature Structural and Molecular Biology 20(9):1033-9
Berndsen CE, Wiener R, Yu IW, Ringel AE, Wolberger C. (2013) A conserved asparagine has a structural role in ubiquitin-conjugating enzymes. Nature Chem Biol. 9: 154-6.
Wiener R, Zhang X, Wang T, Wolberger C. (2012) The mechanism of OTUB1-mediated inhibition of ubiquitination. Nature 483: 618-22.