Titel: Adenovirus large E1B proteins regulate transcription through interaction with mammalian transcription factors
Sprache: Englisch
Autor*in: von Stromberg, Konstantin
Erscheinungsdatum: 2022-12
Tag der mündlichen Prüfung: 2023-01-27
Small human DNA tumor viruses are thought to be the etiological agent for approximately 12% to 20% cancer incidents around the world. The study of this development is quite arduous, as the time frame between primary infection and the emergence of un regulated proliferation of cancer cells is influenced by countless variables and can span multiple decades. One of the hallmarks of human viral tumorigenesis is the evasion of apoptosis and uncontrolled cellular replication, counteracted in part by the tumor suppressor p53 in healthy cells. Circumvention of this important regulatory protein has been observed in many DNA tumor viruses. In order to accomplish this, adenoviruses encode the early region 1B gene region, which contains the E1B-55K protein. It’s main function upon expression lies in the interaction and inhibition of the aforementioned tumor suppressor protein, for which it has evolved multiple synergistic strategies. The currently least understood course of action is its postulated function as a transcriptional repressor of p53-responsive genes, initially hypothesized two decades ago. In this work, I could show an expansive and indirect in vivo occupancy across the host genome of primary baby rat kidney cells through various ChIP-seq experiments. The consequences of this interaction were analyzed by identifying the binding-associated genes and evaluating their respective mRNA expression level via mRNA-seq. These experiments provide tangible evidence that E1B-55K can act as a viral transcriptional repressor by interacting with DNA-bound host transcription factors beyond p53, inhibiting their activity, thereby modulating various downstream responses conducive to a pro-viral environment. I found that this activity is independent from its SUMOylation status, as long as the protein has a means to localize in the nucleus to interact with the host cellular transcriptional machinery. Multiple biological pathway analyses consequently revealed interference with host cell apoptosis, growth inhibition and stress response pathways, among others. This repressive mechanism is highly conserved among large E1B proteins from different adenoviral species and correlates with the observed oncogenicity of the respective viral species. Analysis of the epigenetic landscape of primary human mesenchymal stromal cells that stably expressed E1B-55K provided a potential mechanism of this transcriptional abrogation, as establishment of activating histone PTMs was found to be inhibited at several genomic loci.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/10411
URN: urn:nbn:de:gbv:18-ediss-111163
Dokumenttyp: Dissertation
Betreuer*in: Dobner, Thomas
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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