Univ.-Prof. Dr. rer. nat. Bernhard Lüscher

We are interested in how cell proliferation and differentiation is regulated. In one project we study ADP-ribosylation, a posttranslational modification (PTM) that involves the transfer of ADP-ribose from NAD+ onto substrate proteins. Using the oncoprotein MYC we characterized ARTD10 as a novel interaction partner and defined ARTD10 as the first intracellular mono-ADP-ribosyltransferase. ARTD10 uses substrate-assisted catalysis to modify substrates. We have now identified substrates of ARTD10, established that it controls cell proliferation and apoptosis, and found that ARTD10 regulates the NF-kB signaling pathway. Together, these and other findings highlight the importance of mono-ADP-ribosylation for cell physiology. Further work addresses the biological role of ARTD10 in innate immunity and in tumorigenesis using molecular and cell biological approaches and mouse models.

In a second project we study the regulation of keratinocyte differentation. Atopic dermatitis (AD), a chronic disease with increasing prevalance, results in skin barrier defects. The expression of IL-31 is increased in skin lesions and serum of AD patients and correlates with disease severity. Moreover IL-31 interferes with keratinocyte differentiation in tissue culture. We study the molecular consequences of IL-31 signaling and target genes in 3-dimensional organotypic skin models. Future work will focus on identifying the relevant molecular targets and verifying the functional consequence as well as addressing the therapeutical relevance of the targets.

Verheugd, P., Forst, A. H., Milke, L., Herzog, N., Feijs, K. L. H., Kremmer, E., Kleine, H., and Lüscher, B. 2013. Regulation of NF-k B signaling by the mono-ADP-ribosyltransferase ARTD10. Nature Communications 4, 1683.

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

Menssen, A., Hydbring, P., Kapelle, K., Vervoorts, J., Diebold, J., Lüscher, B., Larsson, L.-G., and Hermeking, H. 2012. c-MYC, NAMPT, DBC-1 and SIRT1 form a regulatory network to antagonize apoptosis and senescence. PNAS 109, E187-196.

Cornelissen, C. Marquardt, Y., Czaja, K., Wenzel, J., Frank, J., Lüscher-Firzlaff, J., Lüscher, B.*, and Baron, J. M.* 2012. IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J. Allergy Clin. Immunol. 129, 426-433e8. *equal contribution

Duncan, J. S., Turowec, J. P., Duncan, K. E., Vilk, G., Wu, C., Lüscher, B., Li, S. S.-C., Gloor, G. B., and Litchfield, D. W. 2011. Deciphering cellular decisions of life and death: Convergence of protein kinase and caspase signaling pathways. Sci Signal. 10;4(172):ra30.

Peters, W., Willnow, S., Duisken, M., Kleine, H., Macherey, T., Duncan, K. E., Litchfield, D. W., Lüscher, B.,* and Weinhold, E.* 2010. Enzymatic site-specific alkyne-functionalization of protein methyltransferase substrates for click labeling. Angewandte Chemie English Edition 49, 5170-5173. *equal contribution

Hydbring, P.*, Bahram, F.*, Su, Y.*, Tronnersjö, S., Högstrand, K., von der Lehr, N., Lilischkis, R., Hein, N., Wu, S., Vervoorts, J., Henriksson, M., Grandien, A., Lüscher, B., and Larsson, L.-G. 2010. Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation. PNAS 107, 58-63. *equal contribution

Arnaud, E., Zenker, J., de Preux Charles, A. S., Stendel, C., Roos, A., Médard, J. J., Tricaud, N., Kleine, H., Lüscher, B., Weis, J., Suter, U., Senderek, J., Chrast, R. 2009. SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system. Proc Natl Acad Sci U S A. 106, 17528-17533.

Kleine, H., Poreba, E., Lesniewicz, K., Hassa, P. O., Hottiger, M. O., Litchfield, D. W., Shilton, B. H., and Lüscher, B. 2008. Substrate-assisted catalysis by PARP10 limits its activity to mono-ADP-ribosylation. Mol. Cell 32, 57-69.

Pandithage*, R., Lilischkis*, R., Harting, K., Wolf, A., Jedamzik, B., Lüscher-Firzlaff, J., Vervoorts, J., Lasonder, E., Kremmer, E., Knöll*, B., and Lüscher*, B. 2008. The regulation of SIRT2 function by Cyclin-dependent kinases affects cell motility. J. Cell Biol. 180, 915-929. *equal contribution

Guccione, E., Bassi, C., Casadio, F., Martinato, F., Cesaroni, M., Schuchlautz, H., Lüscher, B., and Amati, B. 2007. Methylation of histone H3R2 by PRMT6 and H3K4 by MLL complexes are mutually exclusive. Nature 449, 933-937.

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.

Feijs, K. L. H.*, Verheugd, P.*, and Lüscher, B. 2013. Expanding functions of intracellular, resident mono-ADP- ribosylation in cell physiology. FEBS Journal 280, 3519-3529. *equal contribution

Lüscher, B. and Vervoorts, J. 2012. Regulation of gene transcription by the oncoprotein MYC. Gene, 494, 145-160.

Cornelissen, C., Lüscher-Firzlaff, J., Baron, J. M.*, and Lüscher, B*. 2012. Signaling by IL-31 and functional consequences. Eur. J. Cell Biol. 91, 552-566. *equal contribution

Hottiger, M. O., Hassa, P. O., Lüscher, B., Schüler, H., Koch-Nolte, F. 2010. Toward a unified nomenclature for mammalian ADP-ribosyltransferases. TiBS 35, 208-219. All authors contributed equally.

Kleine, H. and Lüscher, B. 2009. Learning how to read ADP-ribosylation. Cell 139, 17-19.