Drosophila p53 directs nonapoptotic programs in postmitotic tissue

Abstract

TP53 is the most frequently mutated gene in human cancers, and despite intensive research efforts, genome-scale studies of p53 function in whole animal models are rare. The need for such in vivo studies is underscored by recent challenges to established paradigms, indicating that unappreciated p53 functions contribute to cancer prevention. Here we leveraged the Drosophila system to interrogate p53 function in a postmitotic context. In the developing embryo, p53 robustly activates important apoptotic genes in response to radiation-induced DNA damage. We recently showed that a p53 enhancer (p53RErpr) near the cell death gene reaper forms chromatin contacts and enables p53 target activation across long genomic distances. Interestingly, we found that this canonical p53 apoptotic program fails to activate in adult heads. Moreover, this failure to exhibit apoptotic responses was not associated with altered chromatin contacts. Instead, we determined that p53 does not occupy the p53RErpr enhancer in this postmitotic tissue as it does in embryos. Through comparative RNA-seq and chromatin immunoprecipitation–seq studies of developing and postmitotic tissues, we further determined that p53 regulates distinct transcriptional programs in adult heads, including DNA repair, metabolism, and proteolysis genes. Strikingly, in the postmitotic context, p53-binding landscapes were poorly correlated with nearby transcriptional effects, raising the possibility that p53 enhancers could be generally acting through long distances.

Polyploidy in the adultDrosophilabrain

“…We did not see a significant difference in the proportion of dead cells in overexpression of p53 WT or p53 DN conditions compared to control (Supp. Fig.5B) consistent with recent work suggesting a non-canonical, non-apoptotic role for p53 in the Drosophila head 51 .…”

“…However the most significantly downregulated GO terms in the OL To further understand the DNA damage and cell cycle signatures observed with age, we looked at the change in expression of specific genes involved in the DNA damage response and the cell cycle ( Fig.5F). Recent work has identified a specific transcriptional response to induced DNA damage in the head that involved a non-canonical role for tumor suppressor protein p53 51 . This signature was termed head Radiation Induced p53-Dependent or hRIPD.…”

Eiger/TNFα-mediated Dilp8 and ROS production coordinate intra-organ growth inDrosophila

“…Consistent with recent reports showing Dmp53 binding to egr locus [32], chromatin immunoprecipitation (ChIP) assays showed that Dmp53 binds to egr and reaper predicted binding sites with similar efficiency ( Figure 3K). Altogether, these results are consistent with Dmp53-activating egr gene expression through a conserved p53 binding site in egr promoter region.…”

Cells with loss-of-heterozygosity after exposure to ionizing radiation in Drosophila are culled by p53-dependent and p53-independent mechanisms

“…Besides its role in apoptosis, Drosophila p53 is known to have multiple non-apoptotic roles including a delay of larval development in response to IR damage [ 19 ], stimulation of Apoptosis-induced-Proliferation in a manner that is independent of its apoptosis-inducing function [ 31 ], reprogramming cellular metabolism during cell competition [ 32 ], and restraining transposon mobility in the germline [ 33 ]. A recent study found that in post-mitotic cells of the adult Drosophila head, p53 regulates transcription programs for DNA repair, proteolysis and metabolism in response to IR [ 34 ]. We do not know what aspect of p53 functions is responsible for culling mwh cells nor do we know when in development this culling occurs because we cannot monitor mwh except in wings near the end of development.…”