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The Structural, Biophysical, and Functional Characterization of the CSL-RITA Complex: Similarities and Differences in Notch Transcriptional Regulation

Tabaja, Nassif H
http://orcid.org/0000-0002-3964-8512
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1479818466222018

Abstract Details

2016, PhD, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
The Notch pathway is an essential component of metazoan development and tissue homeostasis. Dysfunctional Notch signaling has been linked with cardiovascular disease, birth defects, and various cancers. Notch signaling ultimately results in changes in gene expression, which is regulated by the DNA binding protein CSL. CSL functions as both a repressor and activator of transcription from Notch target genes by interacting with transcriptional corepressors and coactivators, respectively. A new transcriptional coregulator has been identified, termed RITA, which binds CSL and facilitates its export out of the nucleus. RITA is thought to function as a corepressor by preventing the assembly of active transcription complexes at Notch target genes. However, the molecular details of the CSL-RITA complex are unknown. In this work, using a combination of biophysical, biochemical/cellular, and structural techniques, we characterize the interaction between CSL and RITA. Chapter 1 is a brief overview of the Notch signaling pathway, from pathway discovery to present day. Chapter 2 contains the structural, biophysical, and functional characterization of the CSL-RITA complex, in which the high affinity interaction between CSL and RITA is demonstrated. Chapter 3 consists of comparative binding analysis of known CSL binding partners using CSL point mutations shown to disrupt CSL activation. Finally, Chapter 4 is a summary of this work as it pertains to future directions in the Notch field.
Rhett Kovall, Ph.D. (Committee Chair)
Kenneth Greis, Ph.D. (Committee Member)
Andrew Herr, Ph.D. (Committee Member)
Anil Menon, Ph.D. (Committee Member)
William Miller, Ph.D. (Committee Member)
263 p.
Molecular Biology
Notch pathway; Notch signaling; CSL; isothermal titration calorimetry; x-ray crystallography; structural biology

Recommended Citations

Citations

  • Tabaja, N. H. (2016). The Structural, Biophysical, and Functional Characterization of the CSL-RITA Complex: Similarities and Differences in Notch Transcriptional Regulation [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1479818466222018

    APA Style (7th edition)

  • Tabaja, Nassif. The Structural, Biophysical, and Functional Characterization of the CSL-RITA Complex: Similarities and Differences in Notch Transcriptional Regulation. 2016. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1479818466222018.

    MLA Style (8th edition)

  • Tabaja, Nassif. "The Structural, Biophysical, and Functional Characterization of the CSL-RITA Complex: Similarities and Differences in Notch Transcriptional Regulation." Doctoral dissertation, University of Cincinnati, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1479818466222018

    Chicago Manual of Style (17th edition)

ucin1479818466222018
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This open access ETD is published by University of Cincinnati and OhioLINK.