Blanca Martínez-Arribas, Cristina E Requena, Guiomar Pérez-Moreno, Luis M Ruíz-Pérez, Antonio E Vidal, Dolores González-Pacanowska
Cellular and molecular life sciences : CMLS 2020 AprTo maintain dNTP pool homeostasis and preserve genetic integrity of nuclear and mitochondrial genomes, the synthesis and degradation of DNA precursors must be precisely regulated. Human all-alpha dCTP pyrophosphatase 1 (DCTPP1) is a dNTP pyrophosphatase with high affinity for dCTP and 5'-modified dCTP derivatives, but its contribution to overall nucleotide metabolism is controversial. Here, we identify a central role for DCTPP1 in the homeostasis of dCTP, dTTP and dUTP. Nucleotide pools and the dUTP/dTTP ratio are severely altered in DCTPP1-deficient cells, which exhibit an accumulation of uracil in genomic DNA, the activation of the DNA damage response and both a mitochondrial and nuclear hypermutator phenotype. Notably, DNA damage can be reverted by incubation with thymidine, dUTPase overexpression or uracil-DNA glycosylase suppression. Moreover, DCTPP1-deficient cells are highly sensitive to down-regulation of nucleoside salvage. Our data indicate that DCTPP1 is crucially involved in the provision of dCMP for thymidylate biosynthesis, introducing a new player in the regulation of pyrimidine dNTP levels and the maintenance of genomic integrity.
Blanca Martínez-Arribas, Cristina E Requena, Guiomar Pérez-Moreno, Luis M Ruíz-Pérez, Antonio E Vidal, Dolores González-Pacanowska. DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools. Cellular and molecular life sciences : CMLS. 2020 Apr;77(8):1645-1660
PMID: 31377845
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