Post-translational Modifications and Cell Proliferation

 

The decision to proliferate or not to proliferate is fundamental for development and healthy maintenance of multicellular organisms. Post-translational modifications (PTMs) such as phosphorylation and ubiquitylation tightly regulate the cell cycle control machinery responsible for this decision-making. PTMs are covalent modifcations of proteins to regulate their function by changing their activity, stability, interactions and localization. Recently, also thiol oxidation of cysteines residues to sulfenic acids emerges as a prime candidate PTM to control cell cycle and proliferation control.

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 identify, visualize and manipulate cell cycle proteins and their PTMs at will.

Cell cycle regulation by reactive oxygen species

 

Long considered as cytotoxic reagents, reactive oxygen species (ROS) at the right concentration promote cell proliferation in cell culture, stem cells and model organisms. However, how ROS signaling is coordinated with cell cycle progression and integrated into the cell cycle control machinery on the molecular level remains unsolved.

Thus, we investigate how reactive oxygen species (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 by using normal and cancer cells as experimental models.

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

Developmental Cell:  https://doi.org/10.1016/j.devcel.2022.06.008

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# (2020).

Science Signaling (13), 654:eaba8208

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, doi: https://doi.org/10.1101/2020.02.03.931196

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.                  

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