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

Cellular and Molecular Life Sciences : CMLS
Blanca Martínez-ArribasDolores González-Pacanowska

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.

References

Apr 1, 1997·Proceedings of the National Academy of Sciences of the United States of America·B C BlountB N Ames
Jan 19, 1999·Annual Review of Microbiology·S I AhmadA Eisenstark
Apr 25, 2000·Molecular and Cellular Biology·C A Torres-RamosS Prakash
May 8, 2003·Cell Cycle·Andrei Chabes, Lars Thelander
Apr 18, 2006·Nucleic Acids Research·Marie GuilletSerge Boiteux
Jul 4, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Christopher K Mathews
Sep 19, 2006·Chemical Research in Toxicology·Silvia TornalettiPhilip C Hanawalt
Apr 4, 2007·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Christopher K Mathews, Shiwei Song
Sep 16, 2008·Molecular Cancer Therapeutics·Peter M WilsonRobert D Ladner
May 26, 2009·Nature Cell Biology·Kok Lung ChanIan D Hickson
Sep 25, 2010·Nucleic Acids Research·András Horváth, Beáta G Vértessy
Oct 22, 2010·Nucleic Acids Research·Dinesh KumarAndrei Chabes
Dec 8, 2011·Methods in Molecular Biology·George E Johnson
Aug 29, 2012·Molecular and Cellular Biology·Arancha SánchezPaul Russell
Oct 3, 2013·European Journal of Histochemistry : EJH·Y ZhangY Wang
Jan 29, 2014·The Biochemical Journal·Cristina E RequenaDolores González-Pacanowska
Jun 15, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Christopher K Mathews
Nov 6, 2014·Genome Research·Patrick EssletzbichlerTilmann Bürckstümmer
Nov 8, 2014·PloS One·Tamami MorisakiKosei Hirakawa
Feb 27, 2015·World Journal of Gastroenterology : WJG·Rajagopal N AravalliClifford J Steer
Jan 16, 2016·Journal of Medicinal Chemistry·Sabin Llona-MinguezThomas Helleday
Jun 22, 2016·The Biochemical Journal·Cristina E RequenaAntonio E Vidal
Feb 2, 2017·Journal of Medicinal Chemistry·Sabin Llona-MinguezThomas Helleday
Feb 2, 2017·Genes·Chen-Chun Pai, Stephen E Kearsey
Mar 16, 2017·Proceedings of the National Academy of Sciences of the United States of America·Claire BouvardShoutian Zhu
May 17, 2017·Journal of Medicinal Chemistry·Sabin Llona-MinguezThomas Helleday

❮ Previous
Next ❯

Citations

Jul 3, 2021·International Journal of Molecular Sciences·Javier RamónRamon Martí

❮ Previous
Next ❯

Methods Mentioned

BETA
transfection
FACS
deamination
fluorescence-activated cell sorting
confocal microscopy

Software Mentioned

GraphPad Prism 5
Fiji
SPSS Statistics

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

© 2021 Meta ULC. All rights reserved