Shared functions of p53 and Xrp1 in DDR and cell competition
Authors: Chaitali Khan 1,2; Nicholas E Baker 1
Affiliations: 1) Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461 ; 2) National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
Keywords: s. cell competition; a. core promoters and general transcription factors
Cell competition is a process of eliminating relatively unfit cells from chimeric tissues. The tumor suppressor gene p53 is implicated in many instances of cell competition in mammals. There is little evidence for this in Drosophila, despite its importance as a model for cell competition. Moreover, mammalian p53 is activated in response to ribosomal defects, whereas Drosophila p53 does not seem to be. We hypothesized in Drosophila a downstream target of p53 carries out some of its functions and additionally receives inputs from cellular stresses that Drosophila p53 does not recognize. This could be the transcription factor Xrp1, a known target of p53, which unlike p53 is activated in response to ribosomal defects and is a key effector of cell competition. Our gene expression analysis shows that Xrp1 is upregulated downstream of p53 in response to acute DNA damage and regulates the expression of molecular players of DNA repair pathway, oxidative response, Jun-kinase signaling and partly the pro-apoptotic gene hid. Further, we show that Xrp1 is necessary and sufficient for the expression of several of p53 target genes, but, we find that Xrp1 is only partly needed for DNA damage-induced cell death. Importantly, by activating p53 in a cell non-lethal manner, we show that differences in p53 levels can cause the elimination of cells with higher p53 when growing next to the cells with lower levels of p53. We perform the two-clone assay to confirm that cells with higher p53 are eliminated by cell competition and that this could occurs by activating Xrp1. Interestingly, removing Xrp1 function to show its role in eliminating cells with higher p53 revealed that Xrp1 not only mediate p53 dependent cell competition but is also needed to restrict the clonal expansion of p53 mutant cells. Which we explained by establishing that Xrp1 acts in a p53- independent manner to limit the passage of aneuploid cells created by DNA damage, via its role in cell competition. This further supports the idea that cell competition eliminates aneuploid cells. Overall, these studies establish a role of the p53 pathway in cell competition in Drosophila as well as mammals, with Xrp1 as a mediator of acute DDR function, cell competition, and genome stability.