TIP60 governs the auto-ubiquitination of UHRF1 through USP7 dissociation from the UHRF1/USP7 complex

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Abstract Background: The epigenetic regulator UHRF1 (Ubiquitin-like, containing PHD and RING finger domains 1) plays an essential role in faithful transmission of DNA methylation during replication. It has tumorogenesis potential and is overexpressed in cancers. TIP60 (Tat interactive protein, 60 kDa) is an important partner of UHRF1, ensuring various cellular processes through its acetyltransferase activity. TIP60 is believed to exert a tumor suppressive role partly explained by its down-regulation in many cancers. Both proteins participate in various cellular functions such as chromatin remodeling, cell cycle, DNA damage repair and regulation of protein stability.Methods: Immunoprecipitation and confocal microscopy techniques were performed to study the ubiquitination of UHRF1 and USP-UHRF1 association. Fluorescence lifetime imaging microscopy (FLIM) technique was performed to analyze the interaction between UHRF1 and ubiquitin inside the nucleus. Western blotting was used to assess the effect of TIP60 overexpression on p73, pro- and anti-apoptotic proteins. TIP60-mediated apoptosis in HeLa cells was investigated by flow cytometry. Results were statistically analyzed using Graphpad prism.Results: Herein, our goal was to investigate the role and mechanism of TIP60 in the regulation of UHRF1 expression. Our results showed that TIP60 overexpression down-regulated UHRF1 and DNMT1 (DNA methyltransferase 1) expressions. TIP60 interfered with USP7-UHRF1 association and induced degradation of UHRF1 in an auto-ubiquitination dependent pathway. Moreover, TIP60 activated the p73-mediated apoptotic pathway.Conclusion: Taken together, our data suggest that the tumor suppressor role of TIP60 is mediated by its regulation to UHRF1.

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