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The role of CRL4 ubiquitin ligase complex in homeostasis and regeneration of gastro intestinal tract
Daněk, Veronika ; Procházka, Jan (advisor) ; Janečková, Lucie (referee) ; Čermák, Lukáš (referee)
Ubiquitination represents a central regulatory mechanism for protein function utilization. Dysfunction of ubiquitin ligases is associated with the development of various pathological conditions. However, the full complexity of the ubiquitinating network in tissue homeostasis and carcinogenesis remains to be elucidated, limiting its potential as a therapeutic target. In my PhD project, I aimed to reveal the role of E3 ubiquitin ligases, particularly CUL4A, in the alteration of regulatory pathways that result in gastrointestinal (GIT) homeostasis disorders and tumor expansion. By using a novel semantic biclustering technique, we performed expression profiling of the E3 ubiquitin ligases and uncovered the potentially redundant features of GIT-specific ubiquitin ligases based on their tissue-specific expression and ontological relationships. Testing the identified compensatory network on the mouse model showed that genes from the same ontology group simultaneously altered their expression pattern after induced epithelial damage, exposing their complementary role during tissue regeneration. Next, I focused on CUL4A, a scaffold of the Cullin4-RING E3 ubiquitin ligase complex (CRL4). We described that CUL4A is expressed by populations of secretory cells in the small intestine and colon. CUL4A deficiency...
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