|Institution:||University of Cincinnati|
|Department:||Medicine: Molecular Genetics, Biochemistry, and Microbiology|
|Keywords:||Biochemistry; Transcriptional Repression; Notch Signaling; Corepressor Complexes; CSL; Structure-Function; KyoT2|
|Full text PDF:||http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406811283|
Collectively, the ubiquitousness and necessity of Notch signaling throughout embryonic development as well as homeostasis of adult tissues highlight the importance of this signaling pathway. Disrupting mutations in any one of the Notch signaling components can result in serious diseases, such as cancer, cardiovascular disease, and developmental malformities. Therefore, understanding on the molecular level how each Notch signaling component, (i.e. DSL, the Notch receptor, and CSL), contributes to the tight transcriptional regulation of Notch target genes is necessary in effectively therapeutically targeting any one of these components. The current focus of our lab is to understand how CSL-coactivator and CSL-corepressor complexes assemble at Notch target genes, and furthermore, how CSL transitions between coactivator and corepressor complexes. The specific contribution of my dissertation was to structurally and thermodynamically characterize two distinct CSL-corepressor complexes—the CSL-KyoT2 complex, and the CSL-MINT-NCoR complex. The comprehensive analysis I have performed on each of these corepressor complexes has shed valuable insight into how CSL interacts with these corepressor proteins to further recruit chromatin remodeling machinery, ultimately resulting in the repression of Notch target genes.