The nucleolar protein NOC1 is essential for ribosome biogenesis, and its reduction activates a novel MYC-p53 axis mediating nucleolar stress

Ribosome biogenesis is a complex cellular process that relies on the coordinated action of numerous nucleolar proteins and RNAs; a crucial step in this mechanism is represented by rRNA processing and maturation. Defects in this process result in a condition known as nucleolar stress, a field of intensive studies for its relation with human diseases. In Drosophila, defects in ribosome production and functionality is associated with the process of cell competition, where cells with impaired ribosome activity are actively killed by the nearby wild-type neighbours; many details related to Drosophila nucleolar stress still need to be characterized. In this work, we explored the functions of a novel Drosophila nucleolar protein named NOC1. We demonstrated that this factor is part of the MYC target network in the nucleolus, regulates rRNA maturation and ribosome subunit functionality, and that it is essential for organismal growth. Reduction of NOC1 in cells of the wing imaginal disc results in MYC upregulation, which drives nucleolar function but also promotes apoptosis. We also show for the first time a regulation between MYC and the transcription factor Xrp1, a master regulator of nucleolar stress and cell competition. p53 is also upregulated in a MYC-Xrp1 dependent manner, and is promoting cell survival and counteracting apoptosis. Indeed, our transcriptomic analysis reveals that NOC1 reduction activates a panel of genes involved in cellular repair pathways, response to DNA damage, and proteotoxic stress. While we have indications that DNA damage is present upon NOC1 downregulation, we still need to clearly determine the processes that regulate apoptosis promotion and survival by MYC, Xrp1 and p53. In epithelial clones, NOC1-reduced cells die by apoptosis, in a mechanism reminiscent of loser cell competition. MYC upregulation in these clones drives apoptosis, which is again counteracted by p53. Therefore, we report a cell competition process in which MYC is not able to drive competitiveness, due to excessive defects in ribosome production. In synthesis, our findings reveal a novel nucleolar stress response caused by the reduction of NOC1 involving MYC and p53 as crucial regulators, along with Xrp1. Since dysregulation of ribosomal activity is implicated in various pathologies, including ribosomopathies and cancer, these results may also provide new insights in the mechanisms that lead to disease development after ribosomal defects.