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Abstract

The c-Myc oncogene regulates the expression of a very large set of genes mainly involved in cell growth and proliferation. This transcription factor has been found to be overexpressed in more than 50% of human cancers, illustrating the importance of keeping its levels and activity under control. The ubiquitin proteasome system is a major regulator of MYC levels in humans as well as in model organisms such as Drosophila melanogaster. Although the E3 ligases that promote MYC ubiquitination have been largely investigated, the identity and the role of the deubiquitinating enzymes which counteract their action is only beginning to be unraveled. Here, we show that the Drosophila homolog of the Ubiquitin Specific Protease USP36 has different isoforms with specific sub-cellular localizations and identify one of them as being required for cell and organismal growth using isoform-specific CRISPR-Cas9 mutagenesis. We also show that this isoform interacts with dMYC and the E3 ligase AGO and regulates their stability and ubiquitination levels. Furthermore, dUSP36 is ubiquitinated by AGO and is able to self-deubiquitinate. Finally we provide in vivo evidence supporting these regulatory relationships. We propose that dMYC, AGO and dUSP36 form a complex that acts as a regulatory node to control dMYC protein levels. Interestingly, this regulatory complex is conserved in humans pointing out its physiological importance.