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

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 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.

Язык: Английский

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SAMHD1 Functions and Human Diseases

Viruses, Год журнала: 2020, Номер 12(4), С. 382 - 382

Опубликована: Март 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.

Язык: Английский

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Alternative promoters drive human cytomegalovirus reactivation from latency

Proceedings of the National Academy of Sciences, Год журнала: 2019, Номер 116(35), С. 17492 - 17497

Опубликована: Авг. 13, 2019

Reactivation from latency requires reinitiation of viral gene expression and culminates in the production infectious progeny. The major immediate early promoter (MIEP) human cytomegalovirus (HCMV) drives crucial lytic cycle transactivators but is silenced during hematopoietic progenitor cells (HPCs). Because MIEP has poor activity HPCs, it unclear how are expressed reactivation. It been presumed that reinitiated via de-repression MIEP. We demonstrate transcripts arising reactivation originate predominantly alternative promoters within canonical locus. Disruption these intronic results striking defects re-expression genes genome replication THP-1 model. Furthermore, we show necessary for efficient primary CD34+ HPCs. Our findings shift paradigm HCMV by demonstrating switching governs a context-specific manner.

Язык: Английский

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Conserved Herpesvirus Protein Kinases Target SAMHD1 to Facilitate Virus Replication

Cell Reports, Год журнала: 2019, Номер 28(2), С. 449 - 459.e5

Опубликована: Июль 1, 2019

Highlights•SAMHD1 depletion facilitates EBV lytic replication•EBV protein kinase BGLF4 directly phosphorylates SAMHD1•BGLF4 phosphorylation of SAMHD1 inhibits its dCTPase and dTTPase activity•SAMHD1 is targeted by the conserved herpesvirus kinasesSummaryTo ensure a successful infection, herpesviruses have developed elegant strategies to counterbalance host anti-viral responses. Sterile alpha motif HD domain 1 (SAMHD1) was recently identified as an intrinsic restriction factor for variety viruses. Aside from HIV-2 related simian immunodeficiency virus (SIV) Vpx proteins, direct viral countermeasures against remain unknown. Using Epstein-Barr (EBV) primary model, we discover that SAMHD1-mediated antagonized BGLF4, member kinases encoded all herpesviruses. Mechanistically, find thereby deoxynucleotide triphosphate triphosphohydrolase (dNTPase) activity. We further demonstrate targeting common feature shared beta- gamma-herpesviruses. Together, our findings uncover immune evasion mechanism whereby exploit thwart defenses.Graphical abstract

Язык: Английский

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Advances in cytomegalovirus (CMV) biology and its relationship to health, diseases, and aging

GeroScience, Год журнала: 2020, Номер 42(2), С. 495 - 504

Опубликована: Март 11, 2020

Язык: Английский

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O-GlcNAcylation and immune cell signaling: A review of known and a preview of unknown

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(6), С. 107349 - 107349

Опубликована: Май 6, 2024

Язык: Английский

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Advances in Model Systems for Human Cytomegalovirus Latency and Reactivation

mBio, Год журнала: 2022, Номер 13(1)

Опубликована: Янв. 11, 2022

Human cytomegalovirus (HCMV) is a highly prevalent beta-herpesvirus and significant cause of morbidity mortality following hematopoietic solid organ transplant, as well the leading viral congenital abnormalities. A key feature pathogenesis HCMV ability virus to establish latent infection in progenitor myeloid lineage cells. The study latency has been hampered by difficulties obtaining culturing primary cells, an inability quantitatively measure reactivating virus, but recent advances both vitro vivo models reactivation have led greater understanding interplay between host virus. Key differences established model systems also controversy surrounding role gene products establishment, maintenance, reactivation. This review will discuss details challenges various including monocytes, cell lines, humanized mice. We highlight utility functional these necessary experimental design required define reactivation, which help generate more complete picture myeloid-lineage

Язык: Английский

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

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Ноя. 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.

Язык: Английский

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SAMHD1 Regulates Human Papillomavirus 16-Induced Cell Proliferation and Viral Replication during Differentiation of Keratinocytes

mSphere, Год журнала: 2019, Номер 4(4)

Опубликована: Авг. 6, 2019

HPVs are causative agents in human cancers and responsible for around of 5% all cancers. A better understanding the viral life cycle keratinocytes will facilitate development novel therapeutics to combat HPV-positive Here, we present a unique keratinocyte model identify host proteins that specifically interact with HPV16. Using this system, report cellular gene, SAMHD1, is regulated by HPV16 at RNA protein levels keratinocytes. Elimination SAMHD1 from these cells using CRISPR/Cas9 editing promotes enhanced proliferation elevated replication but not do have Our study demonstrates specific intricate interplay between during establishes system assist exploring factors critical HPV pathogenesis.

Язык: Английский

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SAMHD1 … and Viral Ways around It

Viruses, Год журнала: 2021, Номер 13(3), С. 395 - 395

Опубликована: Март 2, 2021

The SAM and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase that plays crucial role for variety of different cellular functions. Besides balancing intracellular concentrations, facilitating DNA damage repair, dampening excessive immune responses, SAMHD1 has been shown to act as major restriction factor against various virus species. In addition its well-described activity retroviruses such HIV-1, identified reduce the infectivity viruses herpesviruses CMV EBV, poxvirus VACV, or hepadnavirus HBV. While some are efficiently restricted by SAMHD1, others have developed evasion mechanisms antagonize antiviral SAMHD1. Within this review, we summarize functions highlight countermeasures evolved neutralize

Язык: Английский

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