Replication stress promotes cellular transformation in Drosophila epithelium

The accurate control of DNA replication is crucial for the maintenance of genomic stability and cell viability. In this study, we explore the consequences of depleting the replicative DNA Polymerase α (POLA) in the wing disc of Drosophila melanogaster. Our findings reveal that reduced POLA activity induces DNA replication stress and activates the replication checkpoint in vivo. Consistent with this, we demonstrate that dATR, a key component in DNA replication checkpoint signaling, is essential for the maintenance of tissue integrity under conditions of compromised POLA activity. We show that cells within the wing disc exhibiting reduced POLA activity arrest in the G2 phase and undergo p53-dependent apoptosis. We also reveal a critical role for DNA Ligase 4 in sustaining cell viability when POLA function is impaired. Most notably, we report the appearance of oncogenic traits in wing disc cells with diminished POLA activity when apoptosis is suppressed. In this context, the overexpression of the oncogene cdc25/string enhances the oncogenic phenotype. These results indicate that a combination of oncogenic activation, replication stress, and suppression of apoptosis is sufficient to promote the emergence of hallmarks of tumorigenesis, highlighting major implications for cancer development in humans.