3 ABSTRACT LEDGF/p75 protein is a human transcriptional co-activator and epigenetic reader associated with transcriptionally active chromatin. It is crucial for HIV integration and MLL1 fusion-driven leukemia development. Interactions of LEDGF/p75 with HIV integrase (HIV IN) and MLL1-menin complex are considered an attractive therapeutic target for drug development. LEDGF/p75 interacts with both HIV IN and MLL1-menin complex through its integrase binding domain (IBD). While the pathophysiological interactions of LEDGF/p75 IBD were intensively studied, little was known about the physiological ones. In addition to HIV IN and MLL1, the LEDGF/p75 IBD also interacts with JPO2, PogZ, ASK and MLL2. In search for specific inhibitors of LEDGF/p75 IBD interaction with HIV IN and MLL1, it is essential to obtain detailed information about its interactions with all binding partners. The IBD-MLL1-menin complex has been structurally characterized, but only partially. Using NMR spectroscopy, we identified and mapped a novel part of the IBD-MLL1 interface. This additional interface is able to maintain the interaction between LEDGF/p75 and MLL1 even without the presence of menin, which was considered necessary. Moreover, colony forming assays of primary leukemic blasts revealed that this additional interface is essential for...
| Identifer | oai:union.ndltd.org:nusl.cz/oai:invenio.nusl.cz:347466 |
| Date | January 2016 |
| Creators | Těšina, Petr |
| Contributors | Maloy Řezáčová, Pavlína, Obšil, Tomáš, Spiwok, Vojtěch |
| Source Sets | Czech ETDs |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis |
| Rights | info:eu-repo/semantics/restrictedAccess |
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