KISKER Gruppe

Die Mehrzahl aller Tumore ist auf genetische Schädigungen zurück zu führen. Die Nukleotid-Exzisions-Reparatur ist neben anderen Reparatursystemen für die Erhaltung der korrekten genetischen Information essentiell. Dieses System zeichnet sich auch dadurch aus, dass es DNA-Schädigungen unterschiedlicher Größe reparieren kann. Wir analysieren den Mechanismus der Nukleotid-Exzisions-Reparatur und versuchen zu erklären, wie unterschiedliche Schädigungen erkannt und erfolgreich repariert werden. 

DNA-Reparatur und Drug Design

Ein weiterer Schwerpunkt unserer Arbeitsgruppe ist das "Structure Based Drug Design" gegen pathogene humane Erreger, zum Beispiel im Rahmen der Tuberkuloseforschung, aber auch gegen Staphylococcus aureus, Yersinia pestis oder Burkholderia. Durch die starke Zunahme von Erregern, die gegen existierende Antibiotika resistent sind, ist die Entwicklung neuer Wirkstoffe dringend geboten.

Laborseite

All publications

Zimmermann T, Feng J, de Campos LJ, Knight LA, Schlötzer J, Ramirez YA, Schwickert K, Zehe M, Adler TB, Schirmeister T, Kisker C, Sotriffer C, Conda-Sheridan M, Decker M. Structure-Based Design and Synthesis of Covalent Inhibitors for Deubiquitinase and Acetyltransferase ChlaDUB1 of Clamydia trachomatis. J Med Chem. 2024 Jun 19; doi: 10.1021/cs.jmedchem.4c00230. Online ahead of print. PMID: 38897928

Kuper J, Hove T, Maidl S, Neitz H, Sauer F, Kempf M, Schroeder T, Greiter E, Höbartner C, Kisker C. XPD stalled on cross-linked DNA provides insight into damage verification. Nat Struct Mol Biol. 2024 May 28. doi: 10.1038/s41594-024-01323-5. Epub ahead of print. PMID: 38806694.

Patzke JV, Sauer F, Nair RK, Endres E, Proschak E, Hernandez-Olmos V, Sotriffer C, Kisker C. Structural basis for the bi-specificity of USP25 and USP28 inhibitors. EMBO Rep. 2024 May 30. doi: 10.1038/s44319-024-00167-w. Epub ahead of print. PMID: 38816515.

Richl T, Kuper J, Kisker C. G-quadruplex-mediated genomic instability drives SNVs in cancer. Nucleic Acids Res. 2024 Mar 21;52(5):2198-2211. doi: 10.1093/nar/gkae098.

Kuper J, Kisker C. At the core of nucleotide excision repair. Curr Opin Struct Biol. 2023 Jun;80:102605. doi: 10.1016/j.sbi.2023.102605.

Neitz H, Bessi I, Kuper J, Kisker C, Höbartner C. Programmable DNA interstrand crosslinking by alkene-alkyne [2 + 2] photocycloaddition. J Am Chem Soc. 2023 May 3;145(17):9428-9433. doi: 10.1021/jacs.3c01611.

Humphreys IR, Pei J, Baek M, Krishnakumar A, Anishchenko I, Ovchinnikov S, Zhang J, Ness TJ, Banjade S, Bagde SR, Stancheva VG, Li XH, Liu K, Zheng Z, Barrero DJ, Roy U, Kuper J, Fernández IS, Szakal B, Branzei D, Rizo J, Kisker C, Greene EC, Biggins S, Keeney S, Miller EA, Fromme JC, Hendrickson TL, Cong Q, Baker D. Computed structures of core eukaryotic protein complexes. Science. 2021 Dec 10;374(6573):eabm4805. doi: 10.1126/science.abm4805.

Kappenberger J., Koelmel W., Schoenwetter E., Scheuer T., Woerner J., Kuper J., Kisker C. How to limit the speed of a motor: the intricate regulation of the XPB ATPase and translocase in TFIIH. Nucleic Acids Res. 2020 Dec 2;48(21):12282-12296. doi: 10.1093/nar/gkaa911.

Barnett J.T., Kuper J., Koelmel W., Kisker C., Kad N.M. The TFIIH subunits p44/p62 act as a damage sensor during nucleotide excision repair. Nucleic Acids Res. 2020 Dec 16;48(22):12689-12696. doi: 10.1093/nar/gkaa973.

Peissert S., Schlosser A., Kendel R., Kuper J., Kisker C. Structural basis for CDK7 activation by MAT1 and Cyclin H. Proc Natl Acad Sci U S A. 2020 Oct 27;117(43):26739-26748. doi: 10.1073/pnas.2010885117.

Gerovac M., El Mouali Y., Kuper J., Kisker C., Barquist L., Vogel J. Global discovery of bacterial RNA-binding proteins by RNase-sensitive gradient profiles reports a new FinO domain protein. RNA. 2020 Oct;26(10):1448-1463. doi: 0.1261/rna.076992.120.

Peissert S., Sauer F., Grabarczyk D.B., Braun C., Sander G., Poterszman A., Egly J.M., Kuper J., Kisker C. In TFIIH the Arch domain of XPD is mechanistically essential for transcription and DNA repair. Nat Commun. 2020 Apr 3;11(1):1667. doi: 10.1038/s41467-020-15241-9.

Beckwitt E.C., Jang S., Carnaval Detweiler I., Kuper J., Sauer F., Simon N., Bretzler J., Watkins S.C., Carell T., Kisker C., Van Houten B. Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search. Nat Commun. 2020 Mar 13;11(1):1356. doi: 10.1038/s41467-020-15168-1.

Wollbrink A., Dobel C., Salvari V., Paraskevopoulos E., Kisker C., Mittmann K., Pantev C. Choice of test stimulus matters for pitch matching performance: Comparison between pure tone and narrow band noise. Hear Res. 2019 Sep 15;381:107776. doi: 10.1016/j.heares.2019.107776.

Sauer F., Klemm T., Kollampally R.B., Tessmer I., Nair R.K., Popov N., Kisker C. Differential Oligomerization of the Deubiquitinases USP25 and USP28 Regulates Their Activities. Mol Cell. 2019 May 2;74(3):421-435.e10. doi: 10.1016/j.molcel.2019.02.029.

Nasir N., Kisker C. Mechanistic insights into the enzymatic activity and inhibition of the replicative polymerase exonuclease domain from Mycobacterium tuberculosis. DNA Repair (Amst). 2019 Feb;74:17-25. doi: 10.1016/j.dnarep.2018.12.006.

Ramirez Y.A., Adler T.B., Altmann E., Klemm T., Tiesmeyer C., Sauer F., Kathman S.G., Statsyuk A.V., Sotriffer C., Kisker C. Structural Basis of Substrate Recognition and Covalent Inhibition of Cdu1 from Chlamydia trachomatis. ChemMedChem. 2018 Oct 8;13(19):2014-2023. doi: 10.1002/cmdc.201800364.

Giroud M., Dietzel U., Anselm L., Banner D., Kuglstatter A., Benz J., Blanc J.B., Gaufreteau D., Liu H., Lin X., Stich A., Kuhn B., Schuler F., Kaiser M., Brun R., Schirmeister T., Kisker C., Diederich F., Haap W. (2018). Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors. J Med Chem. 2018 Apr 26;61(8):3350-3369. doi: 10.1021/acs.jmedchem.7b01869. Epub 2018 Apr 13.

Grabarczyk, D.B., Silkenat S., Kisker C. (2018). Structural Basis fort he Recruitment of Ctf18-RFC to the Replisome. Structure 2018 Jan 2;26(1):137-144.e3. doi: 10.1016/j.str.2017.11.004. Epub 2017 Dec 7.

Skinner J.J., Wang S., Lee J., Ong C., Sommese R., Sivaramakrishnan S., Koelmel W., Hirschbeck M., Schindelin H., Kisker C., Lorenz K., Sosnick T.R., Rosner M.R. (2017). Conserved salt-bridge competition triggered by phosphorylation regulates the protein interactome. Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):13453-13458. doi: 10.1073/pnas.1711543114. Epub 2017 Dec 5.

Radu L., Schoenwetter E., Braun C., Marcoux J., Koelmel W., Schmitt D.R., Kuper J., Cianférani S., Egly J.M., Poterszman A., Kisker C. (2017). The intricate network between the p34 and p44 subunits is central to the activity of the transcription/DNA repair factor TFIIH. Nucleic Acids Res. 2017 Oct 13;45(18):10872-10883. doi: 10.1093/nar/gkx743.

Bartossek T., Jones N.G., Schäfer C., Cvitković M., Glogger M., Mott H.R., Kuper J., Brennich M., Carrington M., Smith A.S., Fenz S., Kisker C., Engstler M. (2017). Structural basis for the shielding function of the dynamic trypanosome variant surface glycoprotein coat. Nat Microbiol. 2017 Nov;2(11):1523-1532. doi: 10.1038/s41564-017-0013-6. Epub 2017 Sep 11.

Lu R., Schaefer C.M., Nesbitt N.M., Kuper J., Kisker C., Sampson N.S. (2017). Catabolism of the Cholesterol Side Chain in Mycobacterium tuberculosis ls Controlled by a Redox-Sensitive Thiol Switch. ACS Infect Dis. 2017 Sep 8;3(9):666-675. doi: 10.1021/acsinfecdis.7b00072. Epub 2017 Aug 16.

Kaiser S., Sauer F., Kisker C. (2017). The structural and functional characterization of human RecQ4 reveals insights into its helicase mechanism. Nat Commun. 2017 Jun 27;8:15907. doi: 10.1038/ncomms15907.

Fischer A., Harrison K.S., Ramirez Y., Auer D., Chowdhury S.R., Prusty B.K., Sauer F., Dimond Z., Kisker C., Scott Hefty P., Rudel T. (2017). Chlamydia trachomatis-containing yacuole serves as deubiquitination platform to stabilize Mcl-1 and to interfere with host defense. Elife. 2017 Mar 28;6. pii: e21465. doi: 10.7554/eLife.21465.

Neckles C., Eltschkner S., Cummings J.E., Hirschbeck M., Daryaee F., Bommineni G.R., Zhang Z., Spagnuolo L., Yu W., Davoodi S., Slayden R.A., Kisker C., Tonge P.J. (2017). Rationalizing the Binding Kinetics for the Inhibition of the Burkholderia pseudomallei Fabl1 Enoyl-ACP Reductase. (2017). Biochemistry. 2017 Apr 4;56(13):1865-1878. doi: 10.1021/acs.biochem.6b01048. Epub 2017 Mar 21.

Spagnuolo L.A., Eltschkner S., Yu W., Daryaee F., Davoodi S., Knudson S.E., Allen E.K., Merino J., Pschibul A., Moree B., Thivalapill N., Truglio J.J., Salafsky J., Slayden R.A., Kisker C., Tonge P.J. (2017). Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors. J Am Chem Soc. 2017 Mar 8;139(9):3417-3429. doi: 10.1021/jacs.6b11148. Epub 2017 Feb 22.

Jung L.A., Gebhardt A., Koelmel W., Ade C.P., Walz S., Kuper J., von Eyss B., Letschert S., Redel C., d'Artista L., Biankin A., Zender L., Sauer M., Wolf E., Evan G., Kisker C., Eilers M. (2017). OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors. Oncogene. 2017 Apr 6;36(14):1911-1924. doi: 10.1038/onc.2016.354. Epub 2016 Oct 17.

Daryaee F., Chang A., Schiebel J., Lu Y., Zhang Z., Kapilashrami K., Walker S.G., Kisker C., Sotriffer C.A., Fisher S.L., Tonge P.J. (2017). Correlating Drug-Target Kinetics and In vivo Pharmacodynamics: Long Residence Time Inhibitors of the Fabl Enoyl-ACP Reductase. Chem Sci. 2016 Sep 1;7(9):5945-5954. Epub 2016 May 25.

Lorenzin F., Benary U., Baluapuri A., Walz S., Jung L.A., von Eyss B., Kisker C., Wolf J., Eilers M., Wolf E. (2016). Different promoter affinities account for specificity in MYC-dependent gene regulation.Elife. 2016 Jul 27;5. pii: e15161. doi: 10.7554/eLife.15161. 

Wirth, N., Gross, J., Roth, H.M., Buechner, C.N., Kisker, C., Tessmer, I. (2016) Conversation and Divergence in Nucleotide Excision Repair Lesion Recognition. (2016). J Biol Chem. Jul 12. pii: jbc.M116.739425.

Houten, B.V., Kuper, J., Kisker, C. (2016). Role of XPD in cellular functions: To TFIIH and beyond. DNA Repair (Amst). May 16. pii: S1568-7864(16)30099-4. doi: 10.1016/j.dnarep.2016.05.019.

Neckles,C., Pschibul, A., Lai, C.T., Hirschbeck, M., Kuper, J., Davoodi, S., Zou, J., Liu, N., Pan, P., Shah, S., Daryaee, F., Bommineni, G.R., Lai, C., Simmerling, C., Kisker, C., Tonge, P.J. Selectivity of Pyridone- and Diphenyl Ether-Based Inhibitors for the Yersinia pestis FabV Enoyl-ACP Reductase. Biochemistry. May 31;55(21):2992-3006. doi:10.1021/acs.biochem.5b01301. Epub 2016 May 17.

Rohleder, F., Huang, J., Xue, Y., Kuper, J., Round, A., Seidman, W., Wang, W., Kisker, C. (2016). FANCM interacts with PCNA to promote replication traverse of DNA interstrand crosslinks.Nucleic Acids Res. Pii: gwk037.

Pelz, J.P., Schindelin, H., van Pee, K., Kuper, J., Kisker, C., Diederichs, K., Fischer, U., Grimm, C. (2015). Crystrallizing the 6S and 8S spliceosomal assembly intermediates: a complex project. Acta Crystallogr D Biol Crystallogr. 2015 Oct;71(Pt 10):2040-53. doi: 10.1107/S1399004715014832. Epub 2015 Sep 26.

Koch, S.C., Kuper, J., Gasteiger, K.L., Simon, N., Strasser, R., Eisen, D., Geiger, S., Schneider, S., Kisker, C., Carell, T. (2015). Structural insights into the recognition of cisplatin and AAF-dG lesion by Rad14 (XPA).Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8272-7. doi: 10.1073/pnas.1508509112. Epub 2015 Jun 2.

Schiebel, J., Chang, A., Merget, B., Bommineni, G.R., Yu, W., Spagnuolo, L.A., Baxter, M.V., Tareilus, M., Tonge, P.J., Kisker, C., Sotriffer, C.A. (2015). An ordered water channel in Staphylococcus aureus FabI: unraveling the mechanism of substrate recognition and reduction. Biochemistry. 2015 Mar 17;54(10):1943-55. doi: 10.1021/bi5014358. Epub 2015 Mar 3.

Schaefer, C.M., Lu, R., Nesbitt, N.M., Schiebel, J., Sampson, N.S., and Kisker, C. (2015).  FadA5 a Thiolase from Mycobacterium tuberculosis: A Steroid-Binding Pocket Reveals the Potential for Drug Development against Tuberculosis. Structure 23(1):21-33. Doi: 10.1016/j.str2014.10.010. Epub 2014 Dec 4.

Calebiro, D., Hannawacker, A., Lyga, S., Bathon, K., Zabel, U., Ronchi, C., Beuschlein, F., Reincke, M., Lorenz, K., Alllolio, B., Kisker, C., Fassnacht, M., and Lohse, M.J. (2014). PKA catalytic subunit mutations in adrenocortical Cushing`s adenoma impair association with the regulatory subunit. Nat Commun 5:5680. doi: 10.1038/ncomms6680.

Khan, I., Suhasini, A.N., Banerjee, T., Sommers, J.A., Kaplan, D.L., Kuper, J., Kisker, C., and Brosh, R.M. Jr. (2014). Impact of age-associated cyclopurine lesions on DNA repair helicases. PLoS One 9(11): e113293. doi: 10.1371/journal.pone.0113293. eCollection 2014.

Kuper, J., Braun, C., Elias, A., Michels, G., Sauer, F., Schmitt, D.R., Poterszman, A., Egly, J.M., and Kisker, C. (2014). In TFIIH, XPD helicase is exclusively devoted to DNA repair. PLoS Biol 12(9): e1001954. doi:  10.1371/journal.pbio.1001954. eCollection 2014.

Di Dalmazi, G., Kisker, C., Calebiro, D., Mannelli, M., Canu, L., Arnaldi, G., Quinkler, M., Rayes, N., Tabarin, A., Laure Jullié, M., Mantero, F., Rubin, B., Waldmann, J., Bartsch, D.K., Pasquali, R., Lohse, M., Allolio, B., Fassnacht, M., Beuschlein, F., and Reincke, M. (2014). Novel somatic mutations in the catalytic subunit of the protein kinase A as a cause of adrenal Cushing`s syndrome: a European multicentric study. J Clin Endocrinol Metab. 99(10): E2093-100. doi 10.1210/jc.2014-2152. Epub 2014 Jul 24.

Current positions

• Executive Board Member of the Rudolf Virchow Center (since 2022)
• Vice-President for Research and Academic Development of the University of Würzburg (since 2021)
• Chair of Structural Biology (W3) of University of Würzburg (since 2005)

Previous positions

• Speaker of the Rudolf Virchow Center at the University of Würzburg (2020 - 2021)
• Speaker of the University Senate, University of Würzburg (2019 - 2021)
• President of the German Society for DNA Repair (2018 - 2021)
• Co-Chair Rudolf Virchow Center for Experimental Biomedicine (2016 - 2020)
• Vice Chair Scientific Advisory Board of the Helmholtz Center for Infectious Disease (2012 - 2020)
• Dean Graduate School of Life Sciences of University of Würzburg (2009 - 2021)
• Vice Chair Rudolf Virchow Center for Experimental Biomedicine (2009 - 2016)
• Vice-Dean (Research), Medical Faculty, University of Würzburg (2011 - 2013)

Research Experience

2001 - 2005       Associate Professor, Stony Brook University, Stony Brook, NY, USA
1998 - 2001       Assistant Professor, Stony Brook University, Stony Brook, NY, USA
1994 - 1998       Postdoc, California Institute of Technology, Pasadena, CA, USA

Education

1991 ‐ 1994        Dr. rer. nat. (PhD) Biochemistry, Freie Universität Berlin, Germany
1986 - 1991        Studies in Biochemistry, Free University of Berlin

Honors

• Member of the Bavarian Academy of Sciences (since 2017)
• Member of the German National Academy of Sciences Leopoldina (since 2011)
• 1995 Carl Ramsauer Award for Ph.D. Thesis
• 1995-1997 Postdoctoral Fellowship Deutsche Forschungsgemeinschaft
• 1998-1999 Targeted Research Opportunity Award SUNY Stony Brook
• 2000-2004 PEW Scholar in Biomedical Sciences

Editorial and selected advisory boards

• Member of the „Auswahlausschuss für das Gottfried Wilhelm Leibniz-Programm“ (since 2023)
• Member of the DFG Fachkollegium 201 Basic Research in Biology and Medicine (since 2020)
• Member of the International Advisory Board of the International Institute of Molecular and Cell Biology in Warsaw (since 2020)
• Member of the “Senats and Bewilligungsausschuss für Graduiertenkollegs der DFG” (since 2014 - 2019)
• Member of the Editorial Board NAR Cancer, Oxford University Press (since 2019)
• Member and Speaker of the Senate of the University of Würzburg (since 2019)
• President of the German Society for Research on DNA Repair (since 2018)
• Member of the Bavarian Academy of Sciences (since 2017)
• Member of the “Senats- und Bewilligungsausschuss für Graduiertenkollegs der DFG” (2014 - 2019)
• Reviewer for the European Research Council (2014)
• Member of the scientific advisory Board of the Bavarian Science Foundation (2013)
• Vice-Chair of the Scientific Committee of the Helmholtz-Center for Infection Research, Braunschweig,Germany (2012 - 2020)
• Member of the Scientific Committee of the Helmholtz-Center for Infection Research, Braunschweig, Germany (2012 - 2020)
• Member of the scientific advisory Board of the Bavarian Science Foundation (2013)
• Member of the German National Academy of Sciences Leopoldina (since 2011)
• Vice Chair Structural Biology, Section of the German Society for Biochemistry and Molecular Biology (2007 - 2012)
• Editorial Board DNA Repair (since 2002)

Position
Leiterin - Lehrstuhl für Strukturbiologie am Rudolf-Virchow-Zentrum
Supervisor und Mitglied in verschiedenen Promotionskomitees - Graduate School of Life Sciences/Biomedizin 

Wintersemester

• "Strukturbiologie - Struktur und Funktion biologischer Makromoleküle";  WUESTUDY: 07321010
• "Literaturseminar DNA-Reparatur";  WUESTUDY: 07323480

Sommersemester:

• "Makromolekulare Kristallographie";  WUESTUDY: 07323460
• "Literaturseminar DNA-Reparatur";  WUESTUDY: 07323480