Dual contributions of Xrp1 to genome integrity through the DNA damage response and cell competition

Abstract

Model organisms may help understand how p53 suppresses tumorigenesis in mammals. In Drosophila, the primary transcriptional target of p53 is the gene encoding the bZip AT-hook protein Xrp1, which is another transcription factor. We report that Xrp1 mediates multiple functions of p53 in the DNA damage response (DDR), contributing to p53-dependent gene transcription and DNA damage-induced apoptosis. In addition to this role as a p53 effector, a p53-independent role for Xrp1 in cell competition has been described. Cell competition can remove cells whose genome has been altered by DNA damage and repair. During cell competition, Xrp1 is induced by RpS12, which acts as a sensor of defective ribosome biogenesis. In irradiated discs, p53-independent RpS12-dependent Xrp1 function began as the DDR came to an end, and was even more prominent if p53 function was reduced. Such p53 inhibition resulted in persistence of DNA damage after irradiation, revealed by γH2Av accumulation. Thus, Xrp1 limited the accumulation of abnormal cells resulting from genotoxicity through both the acute, p53-dependent DDR, and also a later mechanism consistent with cell competition removing cells where DNA repair did not restore the normal genome. Both these processes might contribute to the tumor suppressor function of p53 in mammals. Author summary: Accurately maintaining somatic cell genomes helps to prevent cancer. This is accomplished in part by a DNA Damage Response that activates repair genes when DNA damage is detected, and can also kill cells where damage is too extensive. A second mechanism is the selective loss of aneuploid cells even after DNA repair has been completed. The Drosophila transcription factor Xrp1 is expressed in both the DNA Damage Response and in many aneuploid cells. We find that Xrp1 mediates most of the gene expression changes caused by DNA damage, and that both DNA repair and the death of badly damaged cells are less effective without Xrp1. We also extend previous studies of aneuploid cells by showing that Xrp1 function continues to contribute to eliminating cells after DNA damage has been resolved, where Xrp1 is induced by RpS12, a protein that signals decreased ribosomal protein gene dose and initiates cell competition. The synergy between these two processes may offer insight into origins of human cancer. P53, one of the most important human tumor suppressor genes, has both these same functions of marshaling the transcriptional DNA Damage Response as well as stimulating cell competition to remove damaged cells.

Original publication: PLOS Genetics (2026-09-18). Source. Source DOI: 10.1371/journal.pgen.1012309.