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Inhibition of UHRF1 protein by epigenetic partners and epi-drugs

Abstract : UHRF1 is a nuclear protein that is in cancer cells. It plays an essential role in DNA methylation, promotes cell proliferation and inhibits the expression of tumor suppressor genes. TIP60 is an important partner of UHRF1 which participates in chromatin remodeling,transcriptional gene regulation and other cellular activities through its acetyltransferase activity. Both proteins are involved in regulating the activity and stability of important proteins such as DNMT1 and p53. The purpose of this thesis was to study the interaction mechanism of TIP60 with UHRF1 and to explore the effect of over expression of TIP60 inthe regulation of UHRF1 expression. Another objective was to identify and develop UHRF1inhibitors that could target its activity. To achieve these objectives, we used different approaches, including biological and biophysical techniques. The results revealed thatUHRF1 interacts with the MYST domain of TIP60 during the S phase of the cell cycle. The over expression of TIP60 induces the degradation of UHRF1 (an oncogene), in a poly-ubiquitination dependent way, explaining in parts its tumor suppressing role. In addition, an anthraquinone UHRF1 inhibitor was found. This molecule inhibits the flipping activity of methylated cytosine produced by SRA domain of UHRF1. It also altered theUHRF1/DNMT1 interaction and reduced global methylation levels.
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Tanveer Ahmad. Inhibition of UHRF1 protein by epigenetic partners and epi-drugs. Biochemistry, Molecular Biology. Université de Strasbourg, 2019. English. ⟨NNT : 2019STRAJ089⟩. ⟨tel-02882132⟩

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