Intracellular mono-ADP-ribosylation is a recently discovered post-translational mechanism that has been recognized to control various cellular processes. These include DNA repair, NF-κB signaling, the ER stress response, and RNA metabolism. The modification is written by mono-ADPribosyltransferases and erased by mono-ADP-ribosylhydrolases. The latter enzymes use macrodomains for catalysis. Some versions of this domain have also been shown to function as readers of mono-ADP-ribosylation. To study the writters, readers and erasers of this modification, cell-based and mouse models are required. In addition small molecules that interfere with the activities of the factors that are associated with mono-ADP-ribosylation will be required for understanding the biological principales associated with this modification and to evaluate potential translational use.
The trithorax protein ASH2L is an essential subunit of histone H3 lysine 4 (H3Κ4) methyltransferases. The methylation of H3Κ4 is associated with open chromatin and with gene transcription. We want to understand the function of this modification using knockout strategies in cells and animals. We also are interested to further elucidate the role of ASH2L-containing complexes in the control of chromatin and gene transcription. We plan to use genomic screens to define cooperating factors, particularly associated with chromatin function. We also want to develop methods to define substrates of ASH2L-containing methyltransferase complexes beyond histones. This seems particularly relevant for innate immunity and cancer, for DNA repair mechanisms and chromatin regulation.
Support to analyze and evaluate the molecular structures of writers, readers and erasers (relevant for mono-ADP-ribosylation, histone methylation)
to address the catalytic mechanisms using e.g. molecular modeling
to develop small molecules as inhibitors of writers, readers, and erasers to study the biological properties of the targets
to device genetic screens to identify cooperating factors
to expand on the mouse models using disease specific approaches
Forst, A. H., Karlberg, T., Herzog, N., Thorsell, A.-G., Gross, A., Feijs, K. L. H., Verheugd, P., Kursula, P., Nijmeijer, B., Kremmer, E., Kleine, H., Ladurner, A., Schüler, H., and Lüscher, B. 2013. Recognition of mono-ADP-ribosylated ARTD10 substrates by ARTD8 macrodomains. Structure 21, 462–475.
Rosenthal, F.*, Feijs, K. L. H.*, Frugier, E., Bonalli, M., Forst, A. H., Imhof, R., Winkler, H. C., Caflisch, A., Hassa, P. O., Lüscher, B.*, and Hottiger, M. O.* 2013. Macrodomain-containing proteins are novel mono-ADP-ribosylhydrolases. Nature Structural and Molecular Biology 20, 502-507. *equal contribution
Verheugd, P., Forst, A. H., Milke, L., Herzog, N., Feijs, K. L. H., Kremmer, E., Kleine, H., and Lüscher, B. 2013. Regulation of NF-κB signaling by the mono-ADP-ribosyltransferase ARTD10. Nature Communications 4, 1683.
Ullius, A., Lüscher-Firzlaff, J., Costa, I. G., Walsemann, G., Forst, A. H., Gusmao, E. G., Kapelle, K., Kleine, H., Kremmer, E., Vervoorts, J., and Lüscher, B. 2014. The interaction of MYC with the trithorax protein ASH2L promotes gene transcription by regulating H3K27 modification. Nucleic Acids Research 42, 6901-6920.
Treude, F., Kappes, F., Fahrenkamp, D., Müller-Newen, G., Dajas-Bailador, F., Krämer, O. H., Lüscher, B., and Hartkamp, J. 2014. Caspase-8-mediated PAR-4 cleavage is required for TNFα-induced apoptosis. Oncotarget 5, 2988-2998.
Feijs, K. L. H., Forst, A. H., Verheugd, P., and Lüscher, B. 2013. Macrodomain-containing proteins: regulating new intracellular functions of mono(ADP-ribosyl)ation. Nature Reviews Molecular Cell Biology 13, 443-451.