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

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 dC...

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Autores principales: Martínez-Arribas, Blanca, Requena, Cristina E., Pérez-Moreno, Guiomar, Ruíz-Pérez, Luis M., Vidal, Antonio E., González-Pacanowska, Dolores
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162842/
https://www.ncbi.nlm.nih.gov/pubmed/31377845
http://dx.doi.org/10.1007/s00018-019-03250-x
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author Martínez-Arribas, Blanca
Requena, Cristina E.
Pérez-Moreno, Guiomar
Ruíz-Pérez, Luis M.
Vidal, Antonio E.
González-Pacanowska, Dolores
author_facet Martínez-Arribas, Blanca
Requena, Cristina E.
Pérez-Moreno, Guiomar
Ruíz-Pérez, Luis M.
Vidal, Antonio E.
González-Pacanowska, Dolores
author_sort Martínez-Arribas, Blanca
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-019-03250-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-71628422020-04-23 DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools Martínez-Arribas, Blanca Requena, Cristina E. Pérez-Moreno, Guiomar Ruíz-Pérez, Luis M. Vidal, Antonio E. González-Pacanowska, Dolores Cell Mol Life Sci Original Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-019-03250-x) contains supplementary material, which is available to authorized users. Springer International Publishing 2019-08-03 2020 /pmc/articles/PMC7162842/ /pubmed/31377845 http://dx.doi.org/10.1007/s00018-019-03250-x Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Martínez-Arribas, Blanca
Requena, Cristina E.
Pérez-Moreno, Guiomar
Ruíz-Pérez, Luis M.
Vidal, Antonio E.
González-Pacanowska, Dolores
DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools
title DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools
title_full DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools
title_fullStr DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools
title_full_unstemmed DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools
title_short DCTPP1 prevents a mutator phenotype through the modulation of dCTP, dTTP and dUTP pools
title_sort dctpp1 prevents a mutator phenotype through the modulation of dctp, dttp and dutp pools
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162842/
https://www.ncbi.nlm.nih.gov/pubmed/31377845
http://dx.doi.org/10.1007/s00018-019-03250-x
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