SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 7, 2022

Abstract Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) has a dNTPase-independent function in promoting DNA end resection to facilitate double-strand break (DSB) repair by homologous recombination (HR); however, it is not known if upstream signaling events govern this activity. Here, we show that SAMHD1 deacetylated the SIRT1 sirtuin deacetylase, facilitating its binding with ssDNA at DSBs, promote HR. complexes deacetylates conserved lysine 354 (K354) specifically response DSBs. K354 deacetylation promotes HR but tetramerization or dNTPase Mechanistically, recruitment DSBs which turn facilitates CtIP binding, leading promotion of genome integrity. These findings define mechanism governing stability.

Language: Английский

---

Transition State Analysis of SAMHD1 from Primary ¹⁸O, ³³P, and Solvent Kinetic Isotope Effects

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Human sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) is an allosterically regulated dNTP triphosphohydrolase (dNTP + H2O → dNuc PPPi) involved in deoxynucleotide regulation DNA repair. We characterized the chemical features of SAMHD1 transition state for 2′-deoxyadenosine 5′-triphosphate (dATP) hydrolysis by analysis 18O 33P primary kinetic isotope effects (KIEs) at α-phosphoryl leaving triphosphate group. The intrinsic KIE values [5′-18O]dATP 1.028 ± 0.003 [α-33P]dATP 1.015 0.004 provide insights into mechanistic details state. Solvent 2H2O dATP indicate that a single proton being transferred to give solvent 3.2 0.1. Quantum matching supports concerted, loose, highly asymmetric DNAN with Pauling bond order 0.17 attacking hydroxide oxygen nucleophile 0.53 departing deoxyadenosine. reaction coordinate distance 4.7 Å from hydroxyl 5′-deoxyadenosine oxygen. consistent near-midpoint transfer His215 catalytic site donor deoxyadenosine 5′-oxygen This first be use effect characterize phosphotransferase

Language: Английский

---

Roles of SAMHD1 in antiviral defense, autoimmunity and cancer

Reviews in Medical Virology, Journal Year: 2017, Volume and Issue: 27(4)

Published: April 25, 2017

The enzyme, sterile α motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) diminishes infection of human immunodeficiency virus type (HIV-1) by hydrolyzing intracellular deoxynucleotide triphosphates (dNTPs) in myeloid cells resting CD4+ T cells. This dNTP degradation reduces the concentration to a level insufficient for viral cDNA synthesis, thereby inhibiting retroviral replication. antiviral enzymatic activity can be inhibited X (Vpx). HIV-2/SIV Vpx causes SAMHD1, thus interfering with SAMHD1-mediated restriction Recently, SAMHD1 has been suggested restrict HIV-1 directly digesting genomic RNA through still controversial RNase activity. Here, we summarize current knowledge about structure, mechanisms, localization, interferon-regulated expression SAMHD1. We also describe SAMHD1-deficient animal models an drug on basis disrupting proteasomal In addition, possible roles regulating innate immune sensing, Aicardi-Goutières syndrome cancer are discussed this review.

Language: Английский

---

SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: July 28, 2021

Abstract SAMHD1 is a cellular triphosphohydrolase (dNTPase) proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting the supply of dNTP substrates. Yet, phosphorylation T592 downregulates antiviral activity, but not its dNTPase function, implying that additional mechanisms contribute viral restriction. Here, we show SUMOylated on residue K595, modification relies presence proximal SUMO-interacting motif (SIM). Loss K595 SUMOylation suppresses restriction activity SAMHD1, even context constitutively active phospho-ablative T592A mutant has no impact depletion. Conversely, artificial fusion SUMO2 non-SUMOylatable inactive variant restores phenotype reversed phosphomimetic T 592 E mutation. Collectively, our observations clearly establish lack cannot fully account for SAMHD1. We find required stimulate dNTPase-independent cells, an effect antagonized cyclin/CDK-dependent cycling cells.

Language: Английский

---

Attenuation of reverse transcriptase facilitates SAMHD1 restriction of HIV-1 in cycling cells

Retrovirology, Journal Year: 2023, Volume and Issue: 20(1)

Published: May 1, 2023

Abstract Background SAMHD1 is a deoxynucleotide triphosphohydrolase that restricts replication of HIV-1 in differentiated leucocytes. not restricted cycling cells and it has been proposed this due to phosphorylation at T592 these inactivating the enzymatic activity. To distinguish between theories for how but cells, we analysed effects substitutions on restriction dNTP levels both as well tetramer stability activity vitro. Results We first showed was nuclease then characterised panel mutants divided them into three classes. found subset lost their ability restrict which generally corresponded with decrease and/or Interestingly, no were able WT despite being regulated by retaining hydrolyse dNTPs. Lowering addition hydroxyurea did give rise restriction. Compellingly however, RT reduced affinity dNTPs significantly wild-type mutant U937 Jurkat T-cells. Restriction correlated reverse transcription levels. Conclusions Altogether, amino acid residue 592 strong effect formation and, although simple “on/off” switch, does correlate cells. However, preventing lowering adding enough restore Nonetheless, dNTPs, mediated observe time active capable inhibiting if reduced. This suggests very high prevents

Language: Английский

---

Inhibitors of SAMHD1 Obtained from Chemical Tethering to the Guanine Antiviral Acyclovir

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Sterile alpha motif histidine-aspartate domain protein 1 (SAMHD1) is an enzyme with diverse activities. Its dNTPase activity degrades all canonical dNTPs and many anticancer nucleoside drugs, while its single-stranded nucleic acid binding promotes DNA repair RNA homeostasis in cells. These functions require guanine nucleotide to a specific allosteric site (A1) on the enzyme. We previously described how activities of SAMHD1 could be inhibited vitro fragment-based inhibitor design, using dGMP as targeting fragment for A1 site. However, these dGMP-tethered inhibitors had poor cell permeability due charged monophosphate group. Here, we describe new approach where amino form acyclic acyclovir (NH2-ACV) used fragment, allowing facile coupling activated carboxylic acids (R-COOH), either directly or linkers. This generates neutral amide instead attachment points. High-throughput screening ∼375 compound library identified two compounds (8, 11) similar micromolar affinities SAMHD1. Compound 11 was obtained by direct NH2-ACV, 8 five-carbon linker. Both same dibromonaphthol component from screen. A crystal structure complex between 8, combined computational models bound 11, suggest binding. The findings establish that guanine-based do not cyclic structural elements. strategy highly amenable further chemical optimization.

Language: Английский

---

SAMHD1 Impairs HIV-1 Gene Expression and Negatively Modulates Reactivation of Viral Latency in CD4 ⁺ T Cells

Journal of Virology, Journal Year: 2018, Volume and Issue: 92(15)

Published: May 23, 2018

A critical barrier to developing a cure for HIV-1 infection is the long-lived viral reservoir that exists in resting CD4 + T cells, main targets of HIV-1. The maintained through variety mechanisms, including regulation LTR promoter. host protein SAMHD1 restricts replication nondividing but its role latency remains unknown. Here we report new function regulating latency. We found suppressed promoter-driven gene expression and reactivation cell lines primary cells. Furthermore, bound vitro latently infected T-cell line, suggesting binding may negatively modulate Our findings indicate novel latency, which enhances our understanding mechanisms proviral

Language: Английский

---

Are Evolution and the Intracellular Innate Immune System Key Determinants in HIV Transmission?

Frontiers in Immunology, Journal Year: 2017, Volume and Issue: 8

Published: Oct. 6, 2017

HIV-1 is the single most important sexually transmitted disease (STD) in humans from a global health perspective. Among human lentiviruses, M group has uniquely achieved pandemic levels of human-to-human transmission. The requirement to transmit between hosts likely provides strongest selective forces on virus, as without transmission, there can be no new infections within host population. Our perspective that evolution all virus-host interactions, are inherited and perpetuated host-to-host, must consistent with For example, CXCR4 use, which often evolves late infection, does not favour transmission therefore lost when virus transmits host. Thus, inevitably influences aspects biology, including interactions innate immmune system, dictates biological niche exists A viable viral typically select features disfavour immune response represents significant pressure during process. In fact, viruses antagonise and/or evade mechanisms adaptive systems they encounter. We believe viewing host-virus helps us understand mechanistic details antiviral immunity escape. This particularly true for acts very earliest stages interaction, bypassed achieve successful infection. With this mind, here we review sensing HIV, consequent downstream signalling cascades restriction results. centrality these defence illustrated by array counter-measures HIV deploys escape them, despite coding constraint ten kilobase genome. consider evasion strategies detail, particular role capsid accessory proteins highlighting unanswered questions discussing future perspectives.

Language: Английский

---

The Dynamic Interplay between HIV-1, SAMHD1, and the Innate Antiviral Response

Frontiers in Immunology, Journal Year: 2017, Volume and Issue: 8

Published: Nov. 10, 2017

The innate immune response constitutes the first cellular line of defense against initial HIV-1 infection. Immune cells sense invading virus and trigger signaling cascades that induce antiviral defenses to control or eliminate Professional antigen-presenting located in mucosal tissues, including dendritic macrophages, are critical for recognizing at site exposure. These less permissive infection compared activated CD4+ T-cells, which is mainly due host restriction factors serve an immediate role controlling establishment spread viral However, can exploit their avoid detection clearance by system. Sterile alpha motif HD-domain containing protein 1 (SAMHD1) mammalian deoxynucleoside triphosphate triphosphohydrolase (dNTPase) responsible regulating intracellular dNTP pools restricting replication non-dividing myeloid quiescent T-cells. Here, we review analyze latest literature on function SAMHD1, mechanism ability SAMHD1 regulate We also provide overview dynamic interplay between HIV-1, cell-intrinsic elucidate how modulates cells. A more complete understanding SAMHD1's may help develop stratagems enhance its effects, efficiently block pathogenic result

Language: Английский

---

SAMHD 1‐mediated dNTP degradation is required for efficient DNA repair during antibody class switch recombination

The EMBO Journal, Journal Year: 2020, Volume and Issue: 39(15)

Published: June 8, 2020

Language: Английский

---