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Oncogenic role of bromodomain/ATPase containing factor, ATAD2

Abstract : ATAD2 is an evolutionarily conserved but poorly characterized factor that bears different types of func¬tional domains: an AAA ATPase domain and a bromodomain (BRD). ATAD2 is normally highly ex¬pressed in male germ cells and in embryonic stem cells (ESC), however the overexpression of this protein has been detected in a large variety of independent cancers. ATAD2 is proposed to act as a co-activator of androgen and estrogen receptors and in addition, this protein also seems to act as a co-factor for Myc oncogene and plays a role in the pRb/E2F pathway. Moreover, the overexpression of ATAD2 predicts poor prognosis in lung and breast cancers. All of these characteristics make ATAD2 a valuable prognosis biomarker and a promising therapeutic target in aggressive cancers.Herein, we show that hATAD2 binds to acetylated H4 tail through its BRD, and that its ATPase domain enables ATAD2 multimerization, affecting the ability of the BRD to bind acetylated lysine in cells. Additional investigations, including structural studies, show that ATAD2’s BRD is responsible for its specific interaction with acetylated lysine 5 of histone H4. We have also functionally analyzed the AAA ATPase domain and discovered elements that control its role in protein multimerization. In addition, we studied ATAD2 in ESC and in the H1299 lung cancer cell line, and demonstrated that this factor has crucial roles in cell proliferation in the absence of growth factors. Moreover, by using a combination of ChIP-seq, ChIP-proteomics and RNA-seq experiments in ESC, we found that ATAD2 is highly enriched in regions with high transcriptional activity and that it keeps chromatin accessible for chromatin templated factors. These data indicate that ATAD2 in its physiological context ensures a critical role in general chromatin-templated activities, such as transcription, by maintaining the accessibility of chromatin for transcription factors. Finally, in order to structurally characterize either ATAD2 or its homologue in Schizosaccharomyces pombe, ABOI, different fragments containing the AAA ATPase domain were produced in bacteria as well as in insect cells using baculovirus expression vectors. Conditions to produce soluble fragments were established and some of these fragments were purified. Nonetheless, solving the crystal structure of ATAD2 still requires further investigation.
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Mahya Jamshidikia. Oncogenic role of bromodomain/ATPase containing factor, ATAD2. Biochemistry, Molecular Biology. Université Grenoble Alpes, 2017. English. ⟨NNT : 2017GREAV048⟩. ⟨tel-02320656v2⟩

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