Ruprecht-Karls-Universität Heidelberg
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Melchior0218 - Scientist (f/m) / PhD position
Project no:
Melchior0218

Project leader:

Project supervisor:
Melchior, Frauke
Application deadline:
30. Sep 2018
Start of PhD project:
1. Nov 2018

Project description:

Title:
Two projects on: SUMOylation and Ubiquitylation in cell signaling
Summary:
Research in our group centers around posttranslational modification with small ubiquitin-related proteins of the SUMO family. Like ubiquitin, these proteins can be covalently and reversibly linked to other proteins. Reversible protein SUMOylation is an essential process that regulates hundreds of individual proteins in numerous pathways, including cell cycle control, transcription, DNA damage response and oxidative stress. SUMOylation of specific proteins is subject to regulation by other modifications; conversely, SUMO is known to regulate enzymes involved in other posttranslational modifications including phosphorylation, acetylation and ubiquitylation.
We have two PhD student projects available in topics linking SUMOylation to signal transduction in mammalian tissue culture cells. The first project will follow up on the role of a newly identified Ubiquitin E3 ligase in NFκB signaling that interacts with the SUMO E1 enzyme. The ubiquitin E3 ligase can be SUMOylated and binds SUMO non-covalently. Data mining followed by biochemical analyses allowed us to identify a cancer cell line that carries an activating mutation in this E3 ligase, and which has enhanced NFkB signaling. Exploiting this cell line may help to dissect cellular functions and to identify substrates of the E3 ligase. A major aim in this project will be the question how and why this Ubiquitin E3 ligase is regulated by SUMOylation and/or SUMO binding.

The second project follows up on recent findings in the lab that revealed
a novel role for SUMO in EGF receptor signaling: EGF induces transient deSUMOylation and activity changes of a small number of transcription factors. Using microarray analyses and chromatin IP, we could identify genes whose timely expression after EGF is under direct control of this SUMO switch. A major aim in this project will be to dissect signaling events that allow transient deSUMOylation of these transcription factors by EGF and other stimuli. Both projects will require a wide range of biochemical, molecular biological and cell biological methods including, e.g., recombinant expression and purification and in vitro and cell-based analyses of SUMOylation and ubiquitinylation, and may involve proteomics, ChipSeq and RNAseq, CRISPR/Cas9 and others. Both projects may also benefit from further exploitation of cancer-derived mutations.
References:
Review and webinar:
Flotho, F. and Melchior, F. (2013) SUMOylation - a regulatory protein modification in health and disease. Annu. Rev. Biochem. 82, 357-385.

https://www.youtube.com/watch?v=X2AxZu05U4U

Selected original publications:
Stankovic-Valentin, N., Drzewicka, K., König, C., Schiebel, E. and Melchior, F. (2016) Redox-regulation of SUMO enzymes is required for ATM activity and survival in oxidative stress. EMBO J. 35, 1312-1329.

Becker, J., Barysch, S.V., Karaca, S., Dittner, C., Hsiao, H.H., Berriel Diaz, M., Herzig, S., Urlaub, S. and Melchior, F. (2013) Detecting endogenous SUMO targets in mammalian cells and tissues. Nat. Struct. & Mol. Biol. 20, 525-31.

Werner, A., Disanza, A., Reifenberger N, Habeck G., Becker, J., Calabrese, M., Urlaub, H., Lorenz, H., Schulman, B., Scita, G. and Melchior, F. (2013) SCFFbxw5 mediates transient degradation of actin remodeler Eps8 to allow proper mitotic progression. Nat. Cell Biol. 15, 179 -188.
Werner, A.1, Flotho, A.1 and Melchior, F. (2012). Two functionally non-equivalent Ubc9 molecules are required for sumoylation by the RanBP2/RanGAP1*SUMO1/Ubc9 E3 ligase complex. 1 contributed equally. Mol. Cell 46, 287-298.
Methods that will be used:
Cooperation partners:
Personal qualifications:
We are seeking highly motivated PhD students with a strong background in protein biochemistry and cell biology or molecular biology and a broad interest in fundamental aspects of cellular functions. The successful candidates will be part of a very collaborative team of Postdocs, PhD students, Master students and technicians. A special incentive will be membership in one of two collaborative research networks, the SFB 1036 “Cellular Surveillance and damage response” http://www.zmbh.uni-heidelberg.de/sfb1036/ or the TRR 186 "Molecular Switches in the Spatio-Temporal Control of Cellular Signal Transmission" https://trr186.uni-heidelberg.de.
Keywords: