Crystal structures of SAMHD1 inhibitor complexes reveal the mechanism of water-mediated dNTP hydrolysis DOI Creative Commons
E.R. Morris,

Sarah J. Caswell,

Simone Kunzelmann

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: June 23, 2020

Abstract SAMHD1 regulates cellular 2′-deoxynucleoside-5′-triphosphate (dNTP) homeostasis by catalysing the hydrolysis of dNTPs into 2′-deoxynucleosides and triphosphate. In CD4 + myeloid lineage resting T-cells, blocks HIV-1 other viral infections depletion dNTP pool to a level that cannot support replication. mutations are associated with autoimmune disease Aicardi–Goutières syndrome hypermutated cancers. Furthermore, sensitises cancer cells nucleoside-analogue anti-cancer therapies is linked DNA repair suppression interferon response cytosolic nucleic acids. Nevertheless, despite its requirement in these processes, fundamental mechanism SAMHD1-catalysed remained unknown. Here, we present structural enzymological data showing utilises an active site, bi-metallic iron-magnesium centre positions hydroxide nucleophile in-line P α -O 5′ bond catalyse phosphoester hydrolysis. This precise molecular for catalysis, reveals how down-regulates modulates efficacy nucleoside-based anti-viral therapies.

Language: Английский

An Integrated Genome-wide CRISPRa Approach to Functionalize lncRNAs in Drug Resistance DOI Creative Commons
Assaf C. Bester, Jonathan D. Lee, Alejandro Chavez

et al.

Cell, Journal Year: 2018, Volume and Issue: 173(3), P. 649 - 664.e20

Published: April 1, 2018

Language: Английский

Citations

277
Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation DOI Open Access
Torkild Visnes, Armando Cázares‐Körner, Wenjing Hao

et al.

Science, Journal Year: 2018, Volume and Issue: 362(6416), P. 834 - 839

Published: Nov. 15, 2018

The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG because Ogg1-deficient mice are resistant acute systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention treatment inflammation. We developed TH5487, selective active-site inhibitor OGG1, which hampers binding repair well tolerated by mice. TH5487 prevents tumor necrosis factor-α-induced OGG1-DNA interactions at guanine-rich promoters proinflammatory genes. This, turn, decreases occupancy nuclear factor κB gene expression, resulting decreased immune cell recruitment mouse lungs. Thus, present proof concept targeting can alleviate inflammatory conditions vivo.

Language: Английский

Citations

190
SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination DOI Creative Commons
Waaqo Daddacha,

Allyson E. Koyen,

Amanda J. Bastien

et al.

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

Citations

174
SAMHD1 shapes deoxynucleotide triphosphate homeostasis by interconnecting the depletion and biosynthesis of different dNTPs DOI Creative Commons
Claudia McCown, Corey H. Yu, Dmitri N. Ivanov

et al.

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

Citations

3
Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism DOI Open Access

Nikolaos Tsesmetzis,

Cynthia B. J. Paulin, Sean G. Rudd

et al.

Cancers, Journal Year: 2018, Volume and Issue: 10(7), P. 240 - 240

Published: July 23, 2018

Antimetabolites, in particular nucleobase and nucleoside analogues, are cytotoxic drugs that, starting from the small field of paediatric oncology, combination with other chemotherapeutics, have revolutionised clinical oncology transformed cancer into a curable disease. However, even though chemotherapy, together radiation, surgery immunotherapy, can nowadays cure almost all types cancer, we still fail to achieve this for substantial proportion patients. The understanding differences metabolism, pharmacokinetics, pharmacodynamics, tumour biology between patients that be cured cannot, builds scientific basis rational therapy improvements. Here, summarise current knowledge how tumour-specific patient-specific factors dictate resistance nucleobase/nucleoside which strategies re-sensitisation exist. We revisit well-established hurdles treatment efficacy, like blood-brain barrier reduced deoxycytidine kinase activity, but will also discuss role novel factors, such as SAMHD1. A comprehensive appreciation complex mechanisms underpin failure chemotherapy hopefully inform future personalised medicine.

Language: Английский

Citations

114
Cannabis effects on brain structure, function, and cognition: considerations for medical uses of cannabis and its derivatives DOI
Alison C. Burggren, Anaheed Shirazi, Nathaniel D. Ginder

et al.

The American Journal of Drug and Alcohol Abuse, Journal Year: 2019, Volume and Issue: 45(6), P. 563 - 579

Published: July 31, 2019

Background: Cannabis is the most widely used illicit substance worldwide, and legalization for recreational medical purposes has substantially increased its availability use in United States.Objectives: Decades of research have suggested that cannabis confers risk cognitive impairment across various domains, structural functional differences brain been linked to early heavy use.Methods: With substantial evidence role endocannabinoid system neural development understanding continues into adulthood, rising adolescents young adults raises major concerns. Yet some formulations cannabinoid compounds are FDA-approved uses, including applications children.Results: Potential effects on trajectory morphology cognition, therefore, should be considered. The goal this review update consolidate relevant findings order inform attitudes public policy regarding compounds.Conclusions: point considerations age limits guidelines use.

Language: Английский

Citations

103
SAMHD1 Functions and Human Diseases DOI Creative Commons
Si’Ana A. Coggins, Bijan Mahboubi, Raymond F. Schinazi

et al.

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

Citations

82
New strategies to treat AML: novel insights into AML survival pathways and combination therapies DOI
Ramya Nair, Alejandro Salinas-Illarena, Hanna‐Mari Baldauf

et al.

Leukemia, Journal Year: 2020, Volume and Issue: 35(2), P. 299 - 311

Published: Oct. 29, 2020

Language: Английский

Citations

72
Re-Discovery of Pyrimidine Salvage as Target in Cancer Therapy DOI Creative Commons
Melanie Walter, Patrick Herr

Cells, Journal Year: 2022, Volume and Issue: 11(4), P. 739 - 739

Published: Feb. 20, 2022

Nucleotides are synthesized through two distinct pathways: de novo synthesis and nucleoside salvage. Whereas the pathway synthesizes nucleotides from amino acids glucose, salvage recovers nucleosides or bases formed during DNA RNA degradation. In contrast to high proliferating non-malignant cells, which highly dependent on synthesis, cancer cells can switch pathways maintain efficient replication. Pyrimidine remains target of interest in therapy several inhibitors showed promising results vivo models. 1980s 1990s, poor responses were however observed clinical trials with currently existing pyrimidine inhibitors. To overcome limitations trials, targeting alone combination was suggested. Even though this approach initially results, it received fresh attention only recently. Here we discuss re-discovery for replication commonly used antimetabolites various preclinical models trials. We also highlight newly emerged targets as well a immunotherapy.

Language: Английский

Citations

43
SAMHD1 protects cancer cells from various nucleoside-based antimetabolites DOI Creative Commons
Nikolas Herold, Sean G. Rudd, Kumar Sanjiv

et al.

Cell Cycle, Journal Year: 2017, Volume and Issue: 16(11), P. 1029 - 1038

Published: April 24, 2017

Recently, we demonstrated that sterile α motif and HD domain containing protein 1 (SAMHD1) is a major barrier in acute myelogenous leukemia (AML) cells to the cytotoxicity of cytarabine (ara-C), most important drug AML treatment. Ara-C intracellularly converted by canonical dNTP synthesis pathway ara-CTP, which serves as substrate but not an allosteric activator SAMHD1. Using mouse model, show here wild type catalytically inactive SAMHD1 reduces ara-C treatment efficacy vivo. Expanding clinically relevant substrates SAMHD1, demonstrate THP-1 CRISPR/Cas9 lacking functional gene showed increased sensitivity antimetabolites nelarabine, fludarabine, decitabine, vidarabine, clofarabine, trifluridine. Within this Extra View, discuss build upon both these our previously reported findings, propose likely active against variety nucleoside analog present anti-cancer chemotherapies. Thus, may constitute promising target improve wide range therapies for hematological non-haematological malignancies.

Language: Английский

Citations

64