Research overview

Dr Jörg Mansfeld, Post-translational Modifications and Cell Proliferation Team

Deciding when to proliferate or not to proliferate is a fundamental difference between healthy and cancer cells. Post-translational modifications (PTMs) such as phosphorylation and ubiquitylation tightly regulate the cell cycle control machinery responsible for this decision-making. PTMs are covalent modifications of proteins to regulate their function by changing their activity, stability, interactions and localization. Recently, also protein oxidation emerged as a prime PTM to control cell cycle and proliferation control with a high relevance for tumorigenesis.

Within two lines of research our lab combines cell biological and biochemical approaches to reveal how the cell cycle control machinery and thus the decision to continue or halt cell cycle progression is regulated by ubiquitin/ubiquitin-like molecules and thiol oxidation. Since key cell cycle regulators often are targeted by multiple PTMs we are in particular interested in deciphering cross-talk between cell cycle regulatory PTMs.

To enable cutting edge research in the laboratory and translate our findings into potential approaches to treat cancer we routinely develop new technologies and molecules enabling us to identify, visualize and manipulate cell cycle proteins and their PTMs at will. For more information about us including open positions please also have a look at our lab website.

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Cell cycle regulation by reactive oxygen species

Aberrant cell cycle and reduction/oxidation (redox) control are hallmarks of cancer, yet their crosstalk is poorly understood. Reactive oxygen species (ROS) oxidize cysteines to sulfenic acids creating reversible PTMs found on key cell cycle regulators. While this implies that redox changes affect proliferation, the potential of cysteine oxidation as a key cell cycle- regulatory PTM and accordingly as a target for innovative cancer therapies remains unexplored. Redox control of cell proliferation has clear implications for understanding tumour growth, where the redox state of a tumour often differs from normal tissue, and response to radiotherapy that generates ROS. Thus, we investigate using breast cancer as a model how ROS produced by the cell itself or during radiotherapy regulate the cell cycle control machinery and thus the decision to proliferate or not to proliferate.

A ROS-dependent mechanism promotes CDK2 phosphorylation to drive progression through S phase (2022). Kirova DG, Judasova K, Vorhauser J, Zerjatke T, Leung, JK, Glauche I and Mansfeld J. Developmental Cell.

Cell cycle regulation by the ubiquitin system

Within long-standing collaborations with the structural biology laboratory of Sonja Lorenz and the computational structural biology laboratory of Maria T. Pisabarro, we study how complex multiprotein ubiquitin ligases such as the anaphase promoting complex (APC/C) are regulated and can be targeted by molecules, respectively. Recently, we have begun investigating how the poorly understood ubiquitin-like molecule UFM1 regulates cell cycle progression and the decision to proliferate or not to proliferate.

Dimerization regulates the human APC/C-associated ubiquitin-conjugating enzyme UBE2S (2020). Liess AKL, Kucerova A, Schweimer K, Schlesinger D, Dybkov O, Urlaub H, Mansfeld J# and Lorenz S#. Science Signaling (13), 654:eaba8208. #corresponding authors

UFMylation regulates translational homeostasis and cell cycle progression (2020). Gak IA*, Vasiljevic D*, Zerjatke T, Yu L, Brosch M, Roumeliotis TI, Horenburg C, Klemm N, Bakos G, Herrmann A , Hampe J, Glauche I, Choudhary JS and Mansfeld J. BioRxiv.

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Technologies

Quantitative life cell imaging:

Quantitative Cell Cycle Analysis Based on an Endogenous All-in-One Reporter for Cell Tracking and Classification (2017). Zerjatke T., Gak IA., Kirova D., Fuhrmann M., Daniel K., Gonciarz M., Müller D., Glauche I., and Mansfeld J. Cell Reports 19:1-14.

Inducible protein degradation:

Conditional control of fluorescent protein degradation by an auxin-dependent nanobody (2018). Daniel K*, Icha J*, Horenburg C, Müller D, Norden C# and Mansfeld J#. Nature Communications 9:3297. #corresponding authors

PTM identification:

An E2-ubiquitin thioester-driven approach to identify substrates modified with ubiquitin and ubiquitin-like molecules (2018). Bakos, G., Yu l., Gak IA., Roumeliotis, TI., Liakopoulos D., Choudhary JS. and Mansfeld J. Nature Communications 9:4776.

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Research overview Publications