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Rhett Kovall, PhD
Associate Professor of Molecular Genetics
University of Cincinnati College of Medicine
Department of Molecular Genetics, Biochemistry and Microbiology
Cincinnati, OH 45267-0524
My research interests involve understanding at the molecular level how transcription is regulated in the Notch signaling pathway. The Notch pathway is a highly conserved cell-to-cell signaling mechanism in metazoans that is essential for embryonic development and tissue homeostasis. Aberrant Notch signaling underlies the pathogenesis of many human diseases, including congenital defects, cardiovascular disease, and cancer. Notch signaling ultimately results in changes in gene expression, which is regulated by CSL. CSL is a DNA-binding transcription factor that interacts with corepressors and coactivators to regulate transcriptional repression and activation, respectively, of Notch target genes.
My laboratory uses x-ray crystallography to determine the structures of CSL-coregulator complexes, and other biophysical techniques, such as isothermal titration calorimetry (ITC), to characterize the binding and affinity of these complexes. In parallel with these studies, we use cellular and biochemical methods to characterize and functionally validate our structural models. Ultimately, the goal of this research is to provide a molecular explanation for how transcription is regulated in the Notch pathway, which is critical for understanding Notch signaling in normal biological contexts and in diseased states such as cancer.
B.A.: University of Colorado, 1992
Ph.D.: University of Oregon, Institute of Molecular Biology, 1998
Post Graduate Training/Education:
1999-2004, Columbia University Biochemistry & Molecular Biophysics, New York, NY, Postdoctoral fellow in the laboratory of Dr. Wayne A. Hendrickson.
Peer Reviewed Publications (in chronological order):
Contreras, A. N., Yuan, Z., & Kovall, R. A. (2015). Thermodynamic binding analysis of Notch transcription complexes from D. melanogaster. . Protein Science : A Publication of the Protein Society.
Collins, K. J., Yuan, Z., & Kovall, R. A. (2014). Structure and function of the CSL-KyoT2 corepressor complex: a negative regulator of notch signaling. . Structure (London, England : 1993) , 22 (1) , 70-81.
Su, S., Panmanee, W., Wilson, J. J., Mahtani, H. K., Li, Q., Vanderwielen, B. D., Makris, T. M., Rogers, M., McDaniel, C., Lipscomb, J. D., Irvin, R. T., Schurr, M. J., Lancaster, J. R., Kovall, R. A., & Hassett, D. J. (2014). Catalase (KatA) plays a role in protection against anaerobic nitric oxide in Pseudomonas aeruginosa. . PloS One , 9 (3) , e91813.
Torella, R., Li, J., Kinrade, E., Cerda-Moya, G., Contreras, A. N., Foy, R., Stojnic, R., Glen, R. C., Kovall, R. A., Adryan, B., & Bray, S. J. (2014). A combination of computational and experimental approaches identifies DNA sequence constraints associated with target site binding specificity of the transcription factor CSL. . Nucleic Acids Research , 42 (16) , 10550-63.
Yuan, Z., Friedmann, D. R., Vanderwielen, B. D., Collins, K. J., & Kovall, R. A. (2012). Characterization of CSL (CBF-1, Su(H), Lag-1) Mutants Reveals Differences in Signaling Mediated by Notch1 and Notch2. . The Journal of Biological Chemistry , 287 (42) , 34904-16.
Kovall, Rhett A (2012). In notch, one ANK repeat is not like the other. . Structure (London, England : 1993) , 20 (2) , 202-4.
Maier, D., Kurth, P., Schulz, A., Russell, A., Yuan, Z., Gruber, K., Kovall, R. A., & Preiss, A. (2011). Structural and functional analysis of the repressor complex in the Notch signaling pathway of Drosophila melanogaster. . Molecular Biology of the Cell , 22 (17) , 3242-52.
VanderWielen, B. D., Yuan, Z., Friedmann, D. R., & Kovall, R. A. (2011). Transcriptional repression in the Notch pathway: thermodynamic characterization of CSL-MINT (Msx2-interacting nuclear target protein) complexes. . The Journal of Biological Chemistry , 286 (17) , 14892-902.
Bahassi, E. M., Yin, M., Robbins, S. B., Li, Y., Conrady, D. G., Yuan, Z., Kovall, R. A., Herr, A. B., & Stambrook, P. J. (2011). A human cancer-predisposing polymorphism in Cdc25A is embryonic lethal in the mouse and promotes ASK-1 mediated apoptosis. . Cell Division , 6 (1) , 4.
Kurth, P., Preiss, A., Kovall, R. A., & Maier, D. (2011). Molecular analysis of the notch repressor-complex in Drosophila: characterization of potential hairless binding sites on suppressor of hairless. . PloS One , 6 (11) , e27986.
Conrady, D. G., Flagler, M. J., Friedmann, D. R., Vander Wielen, B. D., Kovall, R. A., Weiss, A. A., & Herr, A. B. (2010). Molecular basis of differential B-pentamer stability of Shiga toxins 1 and 2. . PloS One , 5 (12) , e15153.
Kovall, R. A., & Blacklow, S. C. (2010). Mechanistic insights into Notch receptor signaling from structural and biochemical studies. . Current Topics in Developmental Biology , 92 , 31-71.
Friedmann, D. R., & Kovall, R. A. (2010). Thermodynamic and structural insights into CSL-DNA complexes. . Protein Science : A Publication of the Protein Society , 19 (1) , 34-46.
Kovall, R A (2008). More complicated than it looks: assembly of Notch pathway transcription complexes. . Oncogene , 27 (38) , 5099-109.
Friedmann, D. R., Wilson, J. J., & Kovall, R. A. (2008). RAM-induced allostery facilitates assembly of a notch pathway active transcription complex. . The Journal of Biological Chemistry , 283 (21) , 14781-91.
Kovall, Rhett A (2007). Structures of CSL, Notch and Mastermind proteins: piecing together an active transcription complex. . Current Opinion in Structural Biology , 17 (1) , 117-27.
Wilson, J. J., & Kovall, R. A. (2006). Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA. . Cell , 124 (5) , 985-96.
Kovall, R. A., & Hendrickson, W. A. (2004). Crystal structure of the nuclear effector of Notch signaling, CSL, bound to DNA. . The EMBO Journal , 23 (17) , 3441-51.
Min, K. C., Kovall, R. A., & Hendrickson, W. A. (2003). Crystal structure of human alpha-tocopherol transfer protein bound to its ligand: implications for ataxia with vitamin E deficiency. . Proceedings of the National Academy of Sciences of the United States of America , 100 (25) , 14713-8.
Kovall, R. A., & Matthews, B. W. (1999). Type II restriction endonucleases: structural, functional and evolutionary relationships. . Current Opinion in Chemical Biology , 3 (5) , 578-83.
Kovall, R. A., & Matthews, B. W. (1998). Structural, functional, and evolutionary relationships between lambda-exonuclease and the type II restriction endonucleases. . Proceedings of the National Academy of Sciences of the United States of America , 95 (14) , 7893-7.
Rhett Kovall and Brian W. Matthews (1997). Toroidal Structure of Lambda-Exonuclease . Science , 277 (5333) , 1824-1827.
000076 Leukemia Research Foundation. Structure-function of Notch-CSL Transcription Complexes: A Structural Basis for Developing Anti-Leukemia Drugs, PI, Closed.
R01 CA120199 National Cancer Institute. Structure and Function of CSL, the Transcriptional Regulator in the Notch Pathway, PI, Closed.
1278-10 Leukemia & Lymphoma Society. Biophysical Characterization of Notch Pathway Transcription Complexes, PI, Active.
MDA 135618 Muscular Dystrophy Association. Analysis of Notch Transcriptional Mechanisms Required for Muscle Regeneration, PI, Closed.
11PRE7070002 American Heart Association - National Chapter. Thermodynamic, in Vivo, and Structural Analysis of the Notch Pathway CSL-KyoT2 Corepressor Complex, Collaborator, Active.
R01CA178974 National Cancer Institute. Molecular mechanisms of transcriptional regulation in the Notch pathway, PI, Active.
13PRE15570002 American Heart Association - National Chapter. Structure and Function of the MINT/NCoR complex, a novel phosphorylation mechanism that regulates Notch signaling, Collaborator, Active.
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