DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools.
Blanca Martínez-ArribasCristina E RequenaGuiomar Pérez-MorenoLuis M Ruíz-PérezAntonio E VidalDolores Gonzalez PacanowskaPublished in: Cellular and molecular life sciences : CMLS (2019)
To 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.
Keyphrases
- induced apoptosis
- oxidative stress
- dna damage response
- circulating tumor
- dna damage
- dna repair
- cell free
- single molecule
- cell cycle arrest
- endothelial cells
- transcription factor
- endoplasmic reticulum stress
- cell proliferation
- electronic health record
- signaling pathway
- mass spectrometry
- palliative care
- gene expression
- nucleic acid
- machine learning
- living cells