SAMHD1 acts at stalled replication forks to prevent interferon induction

Nature, Journal Year: 2018, Volume and Issue: 557(7703), P. 57 - 61

Published: April 16, 2018

Language: Английский

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Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs

Chemical Reviews, Journal Year: 2016, Volume and Issue: 116(23), P. 14379 - 14455

Published: Nov. 23, 2016

Nucleoside, nucleotide, and base analogs have been in the clinic for decades to treat both viral pathogens neoplasms. More than 20% of patients on anticancer chemotherapy treated with one or more these analogs. This review focuses chemical synthesis biology nucleoside, that are FDA-approved clinical development since 2000. We highlight cellular analogs, drug resistance mechanisms, compound specificity towards different cancer types. Furthermore, we explore analog syntheses as well improved scale-up syntheses. conclude a discussion what might lie ahead medicinal chemists, biologists, physicians they try improve efficacy through prodrug strategies combinations.

Language: Английский

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Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy

Nature Medicine, Journal Year: 2019, Volume and Issue: 25(11), P. 1715 - 1720

Published: Nov. 1, 2019

Language: Английский

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SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination

Cell Reports, Journal Year: 2017, Volume and Issue: 20(8), P. 1921 - 1935

Published: Aug. 1, 2017

Highlights•SAMHD1 deficiency or Vpx-mediated degradation sensitizes cells to DSB-inducing agents•SAMHD1 localizes DNA double-strand breaks in response damage•SAMHD1 promotes HR and end resection independent of its dNTPase activity•SAMHD1 complexes with CtIP facilitates recruitment damage sitesSummaryDNA break (DSB) repair by homologous recombination (HR) is initiated CtIP/MRN-mediated maintain genome integrity. SAMHD1 a dNTP triphosphohydrolase, which restricts HIV-1 infection, mutations are associated Aicardi-Goutières syndrome cancer. We show that has dNTPase-independent function promoting facilitate DSB HR. causes hypersensitivity agents, recruited DSBs. via conserved C-terminal domain recruits DSBs Significantly, cancer-associated mutant impaired interaction, but not dNTPase-inactive SAMHD1, fails rescue the impairment depletion. Our findings define for HR-mediated facilitating accrual promote resection, providing insight into how integrity.Graphical abstract

Language: Английский

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GWAS and ExWAS of blood mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Jan. 13, 2022

Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial (MT) function. The specific biological processes underpinning its regulation, and whether those are causative for disease, area of active investigation.

Language: Английский

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SAMHD1 shapes deoxynucleotide triphosphate homeostasis by interconnecting the depletion and biosynthesis of different dNTPs

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 17, 2025

SAMHD1 is a dNTPase that impedes replication of HIV-1 in myeloid cells and resting T lymphocytes. Here we elucidate the substrate activation mechanism SAMHD1, which involves dNTP binding at allosteric sites transient tetramerization. Our findings reveal tetramerization alone insufficient to promote hydrolysis; instead, requires an inactive tetrameric intermediate with partially occupied sites. The equilibrium between active states regulates activity, driven by dissociation additional ligands preassembled tetramer. Furthermore, catalytic efficiency, but not specificity, modulated identity dNTPs occupying We show how this regulation shapes deoxynucleotide homeostasis balancing production SAMHD1-catalyzed depletion. Notably, exhibits distinct functionality, term facilitated depletion, whereby increased biosynthesis certain enhances depletion others. regulatory relationship different sheds light on emerging role biology implications for HIV/AIDS, innate antiviral immunity, cell disorders, telomere maintenance therapeutic efficacy nucleoside analogs.

Language: Английский

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A Critical Balance: dNTPs and the Maintenance of Genome Stability

Genes, Journal Year: 2017, Volume and Issue: 8(2), P. 57 - 57

Published: Jan. 31, 2017

A crucial factor in maintaining genome stability is establishing deoxynucleoside triphosphate (dNTP) levels within a range that optimal for chromosomal replication. Since DNA replication relevant to wide of other activities, these may all be directly or indirectly affected when dNTP concentrations deviate from physiologically normal range. The importance understanding consequences genetic disorders disturb levels, and strategies inhibit synthesis cancer chemotherapy treatment disorders. We review here how abnormal affect discuss the stability.

Language: Английский

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SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia

Nature Medicine, Journal Year: 2016, Volume and Issue: 23(2), P. 250 - 255

Published: Dec. 19, 2016

Language: Английский

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DNA Replication—A Matter of Fidelity

Molecular Cell, Journal Year: 2016, Volume and Issue: 62(5), P. 745 - 755

Published: June 1, 2016

Language: Английский

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Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies

Nature Medicine, Journal Year: 2017, Volume and Issue: 23(2), P. 256 - 263

Published: Jan. 9, 2017

Language: Английский

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