SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

Autoimmunity, Journal Year: 2018, Volume and Issue: 51(3), P. 96 - 110

Published: March 27, 2018

Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) is a deoxynucleotide triphosphate (dNTP) hydrolase that plays an important role in the homeostatic balance of cellular dNTPs. Its emerging as effector innate immunity affirmed by mutations SAMHD1 gene cause severe autoimmune disease, Aicardi–Goutieres syndrome (AGS) are linked to cancer. Additionally, functions restriction factor for retroviruses, such HIV. Here, we review current biochemical biological properties enzyme including its structure, activity, regulation post-translational modifications context function. We outline open questions regarding biology whose answers will be understanding function regulator cell cycle progression, genomic integrity, autoimmunity.

Language: Английский

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Fragile sites, chromosomal lesions, tandem repeats, and disease

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: Nov. 17, 2022

Expanded tandem repeat DNAs are associated with various unusual chromosomal lesions, despiralizations, multi-branched inter-chromosomal associations, and fragile sites. Fragile sites cytogenetically manifest as localized gaps or discontinuities in chromosome structure an important genetic, biological, health-related phenomena. Common (∼230), present most individuals, induced by aphidicolin can be cancer; of the 27 molecularly-mapped common sites, none a particular DNA sequence motif. Rare ( ≳ 40 known), id="m2">≤ 5% population (may few single individual), neurodevelopmental disease. All 10 folate-sensitive largest category rare caused gene-specific CGG/CCG expansions that aberrantly CpG methylated include FRAXA, FRAXE, FRAXF, FRA2A, FRA7A, FRA10A, FRA11A, FRA11B, FRA12A, FRA16A. The minisatellite-associated FRA10B, FRA16B, AT-rich DNA-ligands nucleotide analogs. Despiralized lesions associations at heterochromatic satellite repeats chromosomes 1, 9, 16 inducible de-methylating agents like 5-azadeoxycytidine spontaneously arise patients ICF syndrome I mmunodeficiency C entromeric instability F acial anomalies) mutations genes regulating methylation. individuals have hypomethylated satellites I-III, alpha-satellites, subtelomeric repeats. Ribosomal D4Z4 megasatellites/macrosatellites, location, fragility, Telomere also assume Dietary deficiencies folate vitamin B12, drug insults megaloblastic and/or pernicious anemia, display recent discovery many new expansion loci, varied motifs, where motif lengths range from mono-nucleotides to megabase units, could molecular cause other lesions. This review focuses on repeat-associated covering their induction, cytogenetics, epigenetics, cell type specificity, genetic (repeat instability, micronuclei, deletions/rearrangements, sister chromatid exchange), heritability, disease association, penetrance. Understanding provides insight structure, genome packaging,

Language: Английский

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P53 suppresses ribonucleotide reductase via inhibiting mTORC1

Oncotarget, Journal Year: 2017, Volume and Issue: 8(25), P. 41422 - 41431

Published: April 26, 2017

Balanced deoxyribonucleotides pools are essential for cell survival and genome stability. Ribonucleotide reductase is the rate-limiting enzyme production of deoxyribonucleotides. We report here that p53 suppresses ribonucleotide subunit 1 (RRM1) 2 (RRM2) via inhibiting mammalian target rapamycin complex (mTORC1). In vitro, cancer lines mouse embryonic fibroblast cells were treated with different concentrations pharmacological inhibitors times. vivo, rhabdomyosarcoma Rh30 tumor-bearing mice or AZD8055. Protein levels phosphorylation status assessed by immunoblotting mRNA determined real time RT-PCR. Pharmacological inhibition mTORC1 rapamycin, mTOR kinase AZD8055 protein B MK2206 resulted in decrease RRM1 RRM2 both vitro tumor xenografts. Moreover, eukaryotic translational initiation factor 4E-binding proteins double knockout demonstrated an elevation RRM2. Furthermore, down-regulation mTOR-protein signaling cyclin dependent 4 led to mRNAs. addition, TP53 mutant had RRM2, which was reduced rapamycin. Importantly, human minute inhibitor nutlin-3 decreased wild type Rh18 but not mutated cells. Our data enhances cap-dependent translation gene transcription findings might provide additional mechanism maintains

Language: Английский

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DCTPP1: A promising target in cancer therapy and prognosis through nucleotide metabolism

Drug Discovery Today, Journal Year: 2025, Volume and Issue: unknown, P. 104348 - 104348

Published: April 1, 2025

Language: Английский

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Understanding the interplay between dNTP metabolism and genome stability in cancer

Disease Models & Mechanisms, Journal Year: 2024, Volume and Issue: 17(8)

Published: Aug. 1, 2024

ABSTRACT The size and composition of the intracellular DNA precursor pool is integral to maintenance genome stability, this relationship fundamental our understanding cancer. Key aspects carcinogenesis, including elevated mutation rates induction certain types damage in cancer cells, can be linked disturbances deoxynucleoside triphosphate (dNTP) pools. Furthermore, approaches treat heavily exploit metabolic interplay between dNTP pool, with a long-standing example being use antimetabolite-based therapies, strategy continues show promise development new targeted therapies. In Review, we compile current knowledge on both causes consequences perturbations together their impact stability. We outline several outstanding questions remaining field, such as role catabolism stability expansion. Importantly, detail how mechanistic these processes utilised aim providing better informed treatment options patients

Language: Английский

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Increased dNTP pools rescue mtDNA depletion in human POLG‐deficient fibroblasts

The FASEB Journal, Journal Year: 2019, Volume and Issue: 33(6), P. 7168 - 7179

Published: March 8, 2019

Polymerase γ catalytic subunit (POLG) gene encodes the enzyme responsible for mitochondrial DNA (mtDNA) synthesis. Mutations affecting POLG are most prevalent cause of disease because defective mtDNA replication and lead to a wide spectrum clinical phenotypes characterized by deletions or depletion. Enhancing deoxyribonucleoside triphosphate (dNTP) synthesis effectively rescues depletion in different models maintenance due dNTP insufficiency. In this study, we studied copy number recovery rates following ethidium bromide-forced quiescent fibroblasts from patients harboring mutations domains POLG. Whereas control cells spontaneously recovered initial levels, POLG-deficient experienced more severe could not repopulate mtDNA. However, activation (dN) salvage supplementation with dNs plus erythro-9-(2-hydroxy-3-nonyl) adenine (inhibitor deoxyadenosine degradation) led increased pools promoted repopulation all tested POLG-mutant independently their specific genetic defect. The treatment did compromise fidelity no increase multiple point was detected. Our study suggests that physiologic concentration limits rate. We thus propose increasing availability be therapeutic interest deficiency other conditions which is challenged.-Blázquez-Bermejo, C., Carreño-Gago, L., Molina-Granada, D., Aguirre, J., Ramón, Torres-Torronteras, Cabrera-Pérez, R., Martín, M. Á., Domínguez-González, de la Cruz, X., Lombès, A., García-Arumí, E., Martí, Cámara, Y. Increased rescue human fibroblasts.

Language: Английский

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A user-friendly, high-throughput tool for the precise fluorescent quantification of deoxyribonucleoside triphosphates from biological samples

Nucleic Acids Research, Journal Year: 2020, Volume and Issue: 48(8), P. e45 - e45

Published: Feb. 17, 2020

Abstract Cells maintain a fine-tuned, dynamic concentration balance in the pool of deoxyribonucleoside 5′-triphosphates (dNTPs). This is essential for physiological processes including cell cycle control or antiviral defense. Its perturbation results increased mutation frequencies, replication arrest and may promote cancer development. An easily accessible relatively high-throughput method would greatly accelerate exploration diversified consequences dNTP imbalances. The incorporation based, fluorescent TaqMan-like assay published by Wilson et al. has aforementioned advantages over mass spectrometry, radioactive chromatography based quantification methods. Nevertheless, failed to produce reliable data several biological samples. Therefore, we applied enzyme kinetics analysis on curves found that Taq polymerase exhibits independent exonuclease activity decouples signal generation from incorporation. Furthermore, both polymerization activities are unpredictably inhibited sample matrix. To resolve these issues, established which identifies generated We automated process nucleoTIDY software enables even inexperienced user calculate final accurate amounts 96-well-plate setup within minutes.

Language: Английский

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Cross-species inhibition of dUTPase via the Staphylococcal Stl protein perturbs dNTP pool and colony formation in Mycobacterium

DNA repair, Journal Year: 2015, Volume and Issue: 30, P. 21 - 27

Published: March 29, 2015

Language: Английский

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Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes

Scientific Reports, Journal Year: 2017, Volume and Issue: 7(1)

Published: July 14, 2017

dUTPase superfamily enzymes generate dUMP, the obligate precursor for de novo dTTP biosynthesis, from either dUTP (monofunctional dUTPase, Dut) or dCTP (bifunctional deaminase/dUTPase, Dcd:dut). In addition, elimination of by these prevents harmful uracil incorporation into DNA. These two beneficial outcomes have been thought to be related. Here we determined relationship between biosynthesis (dTTP/dCTP balance) and prevention DNA uracilation in a mycobacterial model that encodes both Dut Dcd:dut enzymes, has no other ways produce dUMP. We show that, dut mutant mycobacteria, dTTP/dCTP balance remained unchanged, but content increased parallel with vitro activity-loss accompanied considerable increase mutation rate. Conversely, dcd:dut inactivation resulted perturbed two-fold rate, did not Thus, unexpectedly, regulation dNTP are decoupled separately brought about respectively. Available evidence suggests discovered functional separation is conserved humans organisms.

Language: Английский

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Purine auxotrophy: Possible applications beyond genetic marker

Yeast, Journal Year: 2019, Volume and Issue: 36(11), P. 649 - 656

Published: July 23, 2019

Abstract Exploring new drug candidates or targets against many illnesses is necessary as “traditional” treatments lose their effectivity. Cancer and sicknesses caused by protozoan parasites are among these diseases. Cell purine metabolism an important target. Theoretically, inhibiting could stop the proliferation of unwanted cells. Purine similar across all eukaryotes. However, some medically organisms cell lines rely on host metabolism. Protozoans causing malaria, leishmaniasis, toxoplasmosis auxotrophs. Some cancer forms have also lost ability to synthesize purines de novo . Budding yeast can serve effective model for eukaryotic metabolism, thus, auxotrophic strains be tool. In this review, we present common principles in eukaryotes, effects starvation cells, purine‐starved Saccharomyces cerevisiae a depletion‐elicited metabolic states with applications evolution studies pharmacology. behave differently when growing media sufficient supplementation adenine depleted (starvation). latter, they undergo cycle arrest at G1/G0 become stress resistant. Importantly, been observed parasitic protozoans We consider that changes auxotrophy reveal options parasite therapy. Further, knowledge phenotypic will improve use high‐throughput screening primary candidates.

Language: Английский

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