Genomic instability represents a hallmark in carcinogenesis and is also intimately linked to cancer therapy, as many conventional treatments, such as ionizing radiation or chemotherapeutics act by means of their DNA-damaging properties. The cancer “mutanome” has been identified as a predictive marker for response in the context of targeted cancer immunotherapy (i.e. checkpoint inhibitor therapy or vaccinations). Research in the field of genomic instability and DNA repair has been a long-standing core area at the UCT Mainz, which was further strengthened by the foundation of the Institute of Molecular Biology (IMB) at the Johannes Gutenberg University. Tumor mutational burden, neoantigens, copy number alterations or small fusions are linked to the core area Cancer Immunotherapy, providing a strong rationale for collaborative efforts.

• Achievements
• Aims
• Most significant publications

• Scientists from the IMB and the UCT Mainz successfully applied for the SFB 1361 “Regulation of DNA Repair & Genome Stability”, which was initiated in January 2019 and provides an integral resource for translational research projects.

• A state-of-the-art core facility covering all aspects of DNA damage repair e.g. in vivo DNA pathway choice analyses and quantification of DNA damage (comet assays, automated γH2AX staining, functional high-throughput microscopy).

• Research in the core area is focusing on DNA repair pathway choice, e.g. the involvement of nucleotide excision repair in base repair resistant sites (Kitsera N., et al. Nucleic Acid Res. 2019) or the regulation of transcription after toxic UV-light-induced damage (Borisova ME., et al. Nat Commun. 2018). 

• Other groups explore the relationship of epigenetic DNA modifications, transcription and DNA damage, repair and response (Kühn MW., et al. Cancer Discovery. 2016; Göder A., et al. Nat Commun. 2018).

• UCT Mainz investigators demonstrated an essential role of spatial chromosomal folding and active transcription in driving DNA fragility and formation of oncogenic translocations (Gothe HJ., et al. Mol Cell. 2019).

• Aberrant expression of NCAM1 (CD56) on AML blasts was shown to confer resistance, which can be overcome by inhibition of the MAPK-ERK pathway and represents a novel biomarker for targeted therapy in leukemia (Sasca D., et al. Blood. 2019).

• The interrelationship of oncogenic signaling and immune therapy was addressed by Rajalingam group, demonstrating an important role of the CRAF/MAPK pathway in Th17- mediated immunity (Buehler U., et al. EMBO J, 2018).

• Members of the program participate in the TOPART trial exploring the effect of PARP-inhibitors in combination with chemotherapy in solid cancer patients harboring defects in homologous recombination other than BRCA alterations (NCT03127215) and help to identify better biomarkers at a functional level.

The major aim of the UCT Mainz program Genetic Instability & Resistance is to develop novel and rationale combination therapies in close collaborations with the core area Cancer Immunotherapy.  Further, an IIT-concept to target DNA repair in KRASmut lung cancer patients is under evaluation.

• Dzama, M.M., Steiner, M., Rausch, J., Sasca, D., Schönfeld, J., Kunz, K., Taubert, M.C., McGeehan, G.M., Chen, C.W., Mupo, A., Hähnel, P., Theobald, M., Kindler, T., Koche, R.P., Vassiliou, G.S., Armstrong, S.A., Kühn, M.W.M. 2020. Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition. Blood. 136(21), 2442-2456.

• Krishnan, A., Berthelet, J., Renaud, E., Rosigkeit, S., Distler, U., Stawiski, E., Wang, J., Modrusan, Z., Fiedler, M., Bienz, M., Tenzer, S., Schad, A., Roth, W., Thiede, B., Seshagiri, S., Musholt, T.J., Rajalingam, K. 2020. Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas. Nat Commun. 11(1), 2056.

• Kiweler, N., Wunsch, D., Wirth, M., Mahendrarajah, N., Schneider, G., Stauber, R.H., Brenner, W., Butter, F., Kramer, O.H. 2020. Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes. J Cancer Res Clin Oncol. 146(2), 343-356.

• Aasland, D., Götzinger, L., Hauck, L., Berte, N., Meyer, J., Effenberger, M., Schneider, S., Reuber, E.E., Roos, W.P., Tomicic, M.T., Kaina, B., Christmann, M. 2019. Temozolomide Induces Senescence and Repression of DNA Repair Pathways in Glioblastoma Cells via Activation of ATR-CHK1, p21, and NF-κB. Cancer Res. 79(1):99-113. 
   
• Sasca, D., Szybinski, J., Schüler, A., Shah, V., Heidelberger, J., Haehnel, P.S., Dolnik, A., Kriege, O., Fehr, E.M., Gebhardt, W.H., Reid, G., Scholl, C., Theobald, M., Bullinger, L., Beli, P., Kindler, T. 2019. NCAM1 (CD56) promotes leukemogenesis and confers drug resistance in AML. Blood. 133(21):2305-2319.

• Gothe, H.J., Bouwman, B.A.M., Gusmao, E.G., Piccinno, R., Petrosino, G., Sayols, S., Drechsel, O., Minneker, V., Josipovic, N., Mizi, A., Nielsen, C.F., Wagner, E.M., Takeda, S., Sasanuma, H., Hudson, D.F., Kindler, T., Baranello, L., Papantonis, A., Crosetto, N., Roukos, V. 2019. Spatial Chromosome Folding and Active Transcription Drive DNA Fragility and Formation of Oncogenic MLL Translocations. Mol Cell. 75(2):267-283.  

• Gronke, K., Hernández, P.P., Zimmermann, J., Klose, C.S.N., Kofoed-Branzk, M., Guendel, F., Witkowski, M., Tizian, C., Amann, L., Schumacher, F., Glatt, H., Triantafyllopoulou, A., Diefenbach, A. 2019. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature. 566(7743):249-253. 
   
• Borisova, M.E., Voigt, A., Tollenaere, M.A.X., Sahu, S.K., Juretschke, T., Kreim, N., Mailand, N., Choudhary, C., Bekker-Jensen, S., Akutsu, M., Wagner, S.A., Beli, P. 2018. p38-MK2 signaling axis regulates RNA metabolism after UV-lightinduced DNA damage. Nat Commun. 9(1):1017. 
   
• Göder, A., Emmerich, C., Nikolova, T., Kiweler, N., Schreiber, M., Kühl, T., Imhof, D., Christmann, M., Heinzel, T., Schneider, G., Krämer, O.H. 2018. HDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130. Nat Commun. 9(1):764. 
   
• Imre, G., Berthelet, J.,  Heering, J., Kehrloesser, S., Melzer, I.M., Lee, B.I., Thiede, B., Dotsch, V., Rajalingam, K. 2017. Apoptosis inhibitor 5 is an endogenous inhibitor of caspase-2. EMBO Rep. DOI 10.15252/embr.201643744. 

• Kühn, M.W., Song, E., Feng, Z., Sinha, A., Chen, C.W., Deshpande, A.J., Cusan, M., Farnoud, N., Mupo, A., Grove, C., Koche, R., Bradner, J.E., de Stanchina, E., Vassiliou, G.S., Hoshii, T., Armstrong, S.A. 2016. Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia. Cancer Discov. 6(10):1166-1181. 

• Metzig, O., Fuchs, M.D., Tagscherer, K.E., Gröne, H.J., Schirmacher,  P., Roth, W. 2016. Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB. Oncogene. 35(26):3399-409. 
   
• Tomicic, M.T., Meise, R., Aasland, D., Berte, N., Kitzinger, R., Krämer, O.H., Kaina B., Christmann M. 2015. Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM. Oncotarget. 6:33755-68. 



• Deng, S., Yan, T., Nikolova, T., Fuhrmann, D., Nemecek, A., Gödtel-Armbrust, U., Kaina, B., Wojnowski, L. 2015. The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF3 and the DNA damage response in cancer cells. Br J Pharmacol. 172(9), 2246-2257.