Cell-type-specific nucleotide sharing through gap junctions impacts sensitivity to replication stress in Drosophila

Cell proliferation, which underlies tissue growth and homeostasis, requires high levels of metabolites such as deoxynucleotides (dNTPs). The dNTP pool is known to be tightly and cell-autonomously regulated via de novo synthesis and salvage pathways. In this study, we demonstrate that nucleotides can also be provided to cells non-autonomously by surrounding cells within a tissue. Using Drosophila epithelial tissues as models, we find that adult intestinal stem cells (ISCs) are highly sensitive to nucleotide depletion, whereas wing progenitor cells are not. Wing progenitor cells share nucleotides through gap junction connections, allowing buffering of replication stress induced by nucleotide pool depletion. Adult ISCs, however, lack gap junctions and cannot receive dNTPs from neighbors. Collectively, our data suggest that gap-junction-dependent sharing between cells can contribute to dNTP pool homeostasis in vivo. We propose that inherent differences in cellular gap junction permeability can influence sensitivity to fluctuations in intracellular dNTP levels.