The p53 protein takes a two-pronged approach to restraining uncontrolled cell growth — it arrests the cell cycle to block cell proliferation, and activates apoptotic pathways to promote cell death. Or so the story goes. A paper by John Abrams and colleagues in Proceedings of the National Academy of Sciences now adds weight to the argument that this isn't always the case.

The authors were examining the functions of p53 in Drosophila melanogaster (Dmp53) through loss-of-function genetic analysis. They produced a targeted mutation at the Dmp53 locus (Dmp53−ns), and showed that flies with this disruption were viable and fertile, with no observable defects.

To activate programmed cell death in Drosophila, reaper (rpr) is one of three genes that need to be switched on. In response to γ-irradiation, Dmp53 is thought to do this by binding to a radiation-responsive enhancer upstream of rpr. The authors used a rpr–lacZ reporter transgene to show that this activation did not occur in Dmp53−ns mutant embryos, confirming that rpr is a transcriptional target of Dmp53. They also showed that another gene involved in cell death — sickle — was not induced after irradiation in Dmp53−ns mutants, indicating that this might be a Dmp53 target too.

Abrams and colleagues next checked the other side of the response — cell-cycle arrest. They irradiated wing discs, then looked for the presence of cells in mitosis. But they did not observe any cells in mitosis in either wild-type or the Dmp53−ns mutant wing discs after irradiation, suggesting that normal checkpoint functions were unaffected in the Dmp53−ns mutants.

Cells that lack Dmp53 would be expected to show high rates of genomic instability, and the authors confirmed that, in response to moderate doses of ionizing radiation, Dmp53−ns embryos showed considerably more mutagenesis than wild-type embryos. This indicates that Dmp53 can normally preserve genome stability by promoting apoptosis alone, and that failures in cell-cycle arrest are not required to account for genomic instability.

Another implication of these results is an evolutionary one. Similar observations have been made in studies with Caenorhabditis elegans p53, so Abrams and colleagues suggest that “...ancestral functions of p53 were intimately coupled to the regulation of cell death in the face of genotoxic challenge” and that “...an obvious corollary here is that checkpoint arrest by p53 may reflect a more recently invented function, specific perhaps to the vertebrate or mammalian lineage”.