Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors [ChIP-seq]

The role of mitochondrial metabolism in PARPi-mediated anti-tumor therapy remains unexplored. Here, we propose a causal link between mitochondrial NAD+ metabolism and PARPi responsiveness.

In PARPi-non-responsive tumor cells, PARP inhibition specifically expands mitochondrial NADP(H) [mito-NADP(H)] pool, thereby facilitating de novo mitochondrial dTMP (mito-dTMP) biosynthesis and maintaining mitochondrial dTTP (mito-dTTP) pool to prevent uracil misincorporation into mitochondrial DNA (mtDNA), regardless of homologous recombination (HR) status. Mechanistically, loss of PTPN1 ADPRylation by PARPi abolishes its phosphatase activity towards STAT3, yielding enhanced STAT3 phosphorylation and the subsequent transactivation of FoxO1.