TITLE: Mechanisms of ubiquitin signaling in gene regulation and chromatin dynamics
AUTHOR: Cynthia Wolberger, Ph.D., Johns Hopkins University
TIME: 12:00:00 PM DATE: Monday, April 13, 2015
PLACE: Porter Neuroscience Research Center
Live NIH Videocast (archived after seminar)
Professor of Biophysics and Biophysical Chemistry, School of Medicine
Principal Investigator, Wolberger Lab
Cynthia Wolberger is interested in the structural and mechanistic basis for transcriptional regulation and ubiquitin signaling.Her lab focuses on molecular basis for these events, which ensure the integrity and expression of the genome. We use x-ray crystallography, enzymology, cell-based assays and a variety of biophysical tools to gain insights into the mechanisms underlying these essential cellular processes.
Wolberger Webpage: http://pmcb.jhu.edu/faculty/wolberger-profile.html
One of the key ways in which cells dynamically regulate protein function is through reversible post-translational modifications. Lysine residues in particular are subject to a remarkably diverse array of modifications. Our research centers on two types of lysine modification, ubiquitination and acetylation, which play critical role in regulating transcription, the response to DNA damage and intracellular signaling. We use a wide array of approaches including x-ray crystallography, small-angle x-ray scattering, biophysical studies of binding interactions, enzymology and cell-based studies to tackle biological questions.
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.
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, which regulate numerous processes including transcriptional silencing in yeast, lifespan regulation, fat mobilization, and enzyme activity. Recent advances have revealed that sirtuins also remove larger acyl modifications of lysine such as propionyl and succinyl groups, whose biological and mechanistic implications we continue to explore. We use a combination of crystallography and biochemical analysis to study the enzymatic mechanism of these enzymes and how they are regulated by inhibitors and metabolites.
About the Seminars
The NIH Neuroscience Seminar Series features lectures and discussions with leading neuroscientists. Sponsored byNINDS, NIMH, NIA, NIDCD, NIDA, NICHD, NEI, NIAAA,NIDCR, NHGRI and NCCIH, this year’s series offers seminars on aspects of molecular, cellular, developmental and cognitive neuroscience as well as neuroscience related topics in disease, pain and genetics. Seminars are held on the NIH campus on Mondays at noon in the Porter Neuroscience Research Center, Room 620/630, Building 35.