| Autor: |
Martínez-Arribas B; Instituto de Parasitología y Biomedicina 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016, Armilla, Granada, Spain., Requena CE; Instituto de Parasitología y Biomedicina 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016, Armilla, Granada, Spain.; MRC London Institute of Medical Sciences, Du Cane Road, London, W12 0NN, UK.; Institute of Clinical Sciences, Imperial College London, Du Cane Road, London, W12 0NN, UK., Pérez-Moreno G; Instituto de Parasitología y Biomedicina 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016, Armilla, Granada, Spain., Ruíz-Pérez LM; Instituto de Parasitología y Biomedicina 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016, Armilla, Granada, Spain., Vidal AE; Instituto de Parasitología y Biomedicina 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016, Armilla, Granada, Spain., González-Pacanowska D; Instituto de Parasitología y Biomedicina 'López-Neyra', Consejo Superior de Investigaciones Científicas (CSIC), Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, 17, 18016, Armilla, Granada, Spain. dgonzalez@ipb.csic.es. |
| Abstrakt: |
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. |
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