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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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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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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Deoxyribonucleotide metabolism, mutagenesis and cancer

Nature reviews. Cancer, Journal Year: 2015, Volume and Issue: 15(9), P. 528 - 539

Published: Aug. 24, 2015

Language: Английский

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Structural basis of cellular dNTP regulation by SAMHD1

Proceedings of the National Academy of Sciences, Journal Year: 2014, Volume and Issue: 111(41)

Published: Sept. 29, 2014

Significance SAMHD1 is a dNTPase that depletes the cellular dNTP pool to inhibit replication of retroviruses, including HIV-1. The activity also enables enzyme be major regulator levels in mammalian cells, addition implicated pathogenesis chronic lymphocytic leukemia (CLL) and Aicardi Goutières syndrome (AGS). Here we present extensive structural enzymatic data reveal how activated regulated via combined actions GTP all dNTPs. Our work establishes complete spectrum nucleotide binding exquisite regulatory mechanism metabolism, retrovirus restriction, CLL AGS.

Language: Английский

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SAMHD1 is a single-stranded nucleic acid binding protein with no active site-associated nuclease activity

Nucleic Acids Research, Journal Year: 2015, Volume and Issue: 43(13), P. 6486 - 6499

Published: June 22, 2015

The HIV-1 restriction factor SAMHD1 is a tetrameric enzyme activated by guanine nucleotides with dNTP triphosphate hydrolase activity (dNTPase). In addition to this established activity, there have been series of conflicting reports as whether the also possesses single-stranded DNA and/or RNA 3′-5′ exonuclease activity. was purified using three chromatography steps, over which DNase largely separated from dNTPase but RNase persisted. Surprisingly, we found that catalytic and nucleotide activator site mutants no retained activities. Thus, cannot be associated any known binding site. Monomeric bind preferentially RNA, while form required for action bound weakly. ssRNA binding, not ssDNA, induces higher-order oligomeric states are distinct binds dNTPs. We conclude trace activities detected in preparations arise persistent contaminants co-purify HD active An vivo model suggested where alternates between mutually exclusive functions hydrolysis depending on pool levels presence viral ssRNA.

Language: Английский

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Phospho-dependent Regulation of SAMHD1 Oligomerisation Couples Catalysis and Restriction

PLoS Pathogens, Journal Year: 2015, Volume and Issue: 11(10), P. e1005194 - e1005194

Published: Oct. 2, 2015

SAMHD1 restricts HIV-1 infection of myeloid-lineage and resting CD4+ T-cells. Most likely this occurs through deoxynucleoside triphosphate triphosphohydrolase activity that reduces cellular dNTP to a level where reverse transcriptase cannot function, although alternative mechanisms have been proposed recently. Here, we present combined structural virological data demonstrating in addition allosteric activation activity, restriction correlates with the capacity form "long-lived" enzymatically competent tetramers. Tetramer disruption invariably abolishes but has varied effects on vitro activity. phosphorylation also ablates tetramer formation without affecting steady-state kinetics. However phospho-SAMHD1 is unable catalyse turnover under conditions nucleotide depletion. Based our findings propose model for phosphorylation-dependent regulation dephosphorylation switches housekeeping found cycling cells high-activity stable tetrameric depletes maintains low levels dNTPs differentiated cells.

Language: Английский

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SAMHD1 Functions and Human Diseases

Viruses, Journal Year: 2020, Volume and Issue: 12(4), P. 382 - 382

Published: March 31, 2020

Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells a variety viral pathogens. While process dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) thymidine kinase (TK), has been extensively investigated, negative regulatory mechanism pools was recently found to involve sterile alpha motif (SAM) domain histidine-aspartate (HD) domain-containing protein 1, SAMHD1. When active, triphosphohydrolase activity SAMHD1 degrades dNTPs into their 2'-deoxynucleoside (dN) subparts, steadily depleting intercellular pools. The differential expression levels activation states various cell types contributes unique that either aid (i.e., dividing T cells) or restrict nondividing macrophages) consumes dNTPs. Genetic mutations induce rare inflammatory encephalopathy called Aicardi-Goutières syndrome (AGS), which phenotypically resembles infection. Recent publications have identified diverse roles double-stranded break repair, genome stability, stress response through interferon signaling. Finally, series were also reported cancer while why is mutated these remains investigated. Here, we reviewed studies begun illuminating highly virology, immunology, biology.

Language: Английский

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Deoxyribonucleotides as genetic and metabolic regulators

The FASEB Journal, Journal Year: 2014, Volume and Issue: 28(9), P. 3832 - 3840

Published: June 13, 2014

For >35 yr, we have known that the accuracy of DNA replication is controlled in large part by relative concentrations 4 canonical deoxyribonucleoside 5'-triphosphates (dNTPs) at replisome. Since this field was last reviewed, ∼8 yr ago, there has been increased understanding mutagenic pathways as they occur living cells. At same time, aspects deoxyribonucleotide metabolism shown to be critically involved processes diverse cell cycle control, protooncogene expression, cellular defense against HIV infection, rate telomere length and mitochondrial function. Evidence supports a relationship between dNTP pools microsatellite repeat instability. Relationships synthesis breakdown controlling steady-state become better defined. In addition, new experimental approaches allowed definitive analysis mutational induced pool abnormalities, both Escherichia coli yeast. Finally, ribonucleoside triphosphate (rNTP) critical determinants fidelity. These developments are discussed review article.

Language: Английский

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CyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain

Journal of Biological Chemistry, Journal Year: 2015, Volume and Issue: 290(21), P. 13279 - 13292

Published: April 7, 2015

Language: Английский

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