Nucleotide sharing through gap junctions buffers replication stress

Abstract

Cell proliferation underlying tissue growth and homeostasis, requires high levels of metabolites such as deoxynucleotides (dNTPs). The dNTP pool is known to be tightly cell-autonomously regulated through thede novosynthesis and salvage pathways. Here, we reveal that nucleotides can be provided to cells non-autonomously by surrounding cells of the tissue.Drosophilaadult intestinal stem cells are highly sensitive to nucleotide depletion whereas wing progenitor cells are not. While adult intestinal stem cells lack gap junctions and their associated capacity to buffer dNTP pools, wing progenitor cells share nucleotides through connections to surrounding cells via gap junctions, allowing buffering of replication stress induced by nucleotide pool depletion. These findings have broad implications, suggesting that gap junction connectivity may define how sensitive cells are to changes in intracellular dNTP levels and replication stress.