DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools.

DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools.
Cell Mol Life Sci. 2019 Aug 03;:
Authors: Martínez-Arribas B, Requena CE, Pérez-Moreno G, Ruíz-Pérez LM, Vidal AE, González-Pacanowska D
Abstract
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.
PMID: 31377845 [PubMed - as supplied by publ...

Source: Cellular and Molecular Life Sciences : CMLS - August 2, 2019 Category: Cytology Authors: Martínez-Arribas B, Requena CE, Pérez-Moreno G, Ruíz-Pérez LM, Vidal AE, González-Pacanowska D Tags: Cell Mol Life Sci Source Type: research