Altered dNTP pools accelerate tumor formation in mice

Abstract

Alterations in deoxyribonucleoside triphosphate (dNTP) pools have been linked to increased mutation rates and genome inst abilit y in unicellular organisms and cell cultures. Ho w e v er, the role of dNTP pool changes in tumor de v elopment in mammals remains unclear. In this study, we present a mouse model with a point mutation at the allosteric specificity site of ribonucleotide reductase, RRM1-Y285A. This mutation reduced ribonucleotide reduct ase activit y, impairing the synthesis of deo xy adenosine triphosphate (dATP) and deo xy guanosine triphosphate (dGTP). Heterozygous Rrm1 + / Y285A mice exhibited distinct alterations in dNTP pools across various organs, shorter lifespans and earlier tumor onset compared with wild-type controls. Mutational spectrum analysis of tumors revealed two distinct signatures, one resembling a signature extracted from a human cancer harboring a mutation of the same amino acid residue in ribonucleotide reductase, RRM1 Y285C . Our findings suggest that mutations in enzymes in v olv ed in dNTP metabolism can serve as drivers of cancer development.