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Summary: Nucleotide deprivation and imbalance present detrimental conditions for animals and are thus expected to trigger cellular responses that direct protective changes in metabolic, developmental, and behavioral programs, albeit such mechanisms are vastly underexplored. Following our previous finding that Caenorhabditis elegans shut down germ cell proliferation in response to pyrimidine deprivation, we find in this study that endonuclease ENDU-2 regulates nucleotide metabolism and germ cell proliferation in response to nucleotide imbalance and other genotoxic stress, and that it affects mitotic chromosomal segregation in the intestine and lifespan. ENDU-2 expression is induced by nucleotide imbalance and genotoxic stress, and ENDU-2 exerts its function in the intestine, mostly by inhibiting the phosphorylation of CTPS-1 through repressing the PKA pathway and histone deacetylase HDA-1. Human EndoU also affects the response to genotoxic drugs. Our work reveals an unknown role of ENDU-2 in regulating nucleotide metabolism and animals’ response to genotoxic stress, which may link EndoU function to cancer treatment. : Jia et al. show that an endonuclease plays a critical role in a nucleotide response system in nematodes and possibly mammalian cells. It affects nucleotide metabolism and reproductive development in response to nucleotide imbalance or other stresses, and it does so by inhibiting the phosphorylation of CTP synthase in the gut. Keywords: EndoU, CTP synthase, ENDU-2, CTPS-1, cytidine deaminase, protein kinase A, histone deacetylase, CTPS phosphorylation, nucleotide sensing, nucleotide imbalance