Altered dNTP Pools Accelerate Tumor Formation in Mice

Changes in dNTP pools have long been associated with increased mutation rates and genome instability in unicellular organisms and cell cultures. However, the extent to which alterations in dNTP pools can trigger tumor development in mammals remains unclear. Here, we present a mouse model in which we introduced a point mutation at the allosteric specificity site of ribonucleotide reductase--an enzyme critical for dNTP pool production and maintenance. This mutation resulted in reduced ribonucleotide reductase activity, negatively affecting dATP and dGTP synthesis. Heterozygous mutant mice exhibited distinct alterations in dNTP pools across various organs, along with shorter lifespan and earlier onset of tumors compared to wild-type controls. Mutational spectrum analysis of tumors revealed two distinct signatures, one of them closely resembling a signature extracted from a human cancer harboring a mutation of the same amino acid residue in ribonucleotide reductase. Our findings suggest that perturbations in dNTP pools, which can arise from defects in multiple genes, may serve as drivers of cancer development.