Single-Stranded Nucleic Acids Bind to the Tetramer Interface of SAMHD1 and Prevent Formation of the Catalytic Homotetramer DOI
Kyle J. Seamon, Namandjé N. Bumpus, James T. Stivers

et al.

Biochemistry, Journal Year: 2016, Volume and Issue: 55(44), P. 6087 - 6099

Published: Oct. 24, 2016

Sterile alpha motif and HD domain protein 1 (SAMHD1) is a unique enzyme that plays important roles in nucleic acid metabolism, viral restriction, the pathogenesis of autoimmune diseases cancer. Although much attention has been focused on its dNTP triphosphohydrolase activity restriction disease, SAMHD1 also binds to single-stranded RNA DNA. Here we utilize UV cross-linking method using 5-bromodeoxyuridine-substituted oligonucleotides coupled with high-resolution mass spectrometry identify binding site for acids (ssNAs) SAMHD1. Mapping cross-linked amino surface existing crystal structures demonstrated ssNA lies largely along dimer-dimer interface, sterically blocking formation homotetramer required dNTPase activity. Surprisingly, disordered C-terminus (residues 583-626) was implicated binding. An interaction between this region confirmed studies purified 583-626 peptide. Despite recent report possesses polyribonucleotide phosphorylase activity, did not detect any such presence inorganic phosphate, indicating unrelated proposed These data suggest an antagonistic regulatory mechanism which mutually exclusive oligomeric state requirements hydrolase modulate these two functions within cell.

Language: Английский

SAMHD1 acts at stalled replication forks to prevent interferon induction DOI
Flavie Coquel, Maria João Silva, Hervé Técher

et al.

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

Published: April 16, 2018

Language: Английский

Citations

385
Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs DOI

Jadd R. Shelton,

Xiao Lu,

Joseph A. Hollenbaugh

et al.

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

Citations

332
Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy DOI
Diego Chowell, Chirag Krishna, Federica Pierini

et al.

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

Published: Nov. 1, 2019

Language: Английский

Citations

258
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
GWAS and ExWAS of blood mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia DOI Creative Commons
Michael Chong, Pedrum Mohammadi‐Shemirani, Nicolas Perrot

et al.

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

Citations

84
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
A Critical Balance: dNTPs and the Maintenance of Genome Stability DOI Open Access
Chen‐Chun Pai, Stephen Kearsey

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

Citations

150
SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia DOI

Constanze Schneider,

Thomas Oellerich, Hanna‐Mari Baldauf

et al.

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

Published: Dec. 19, 2016

Language: Английский

Citations

149
DNA Replication—A Matter of Fidelity DOI Creative Commons

Rais A. Ganai,

Erik Johansson

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

Published: June 1, 2016

Language: Английский

Citations

137
Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies DOI
Nikolas Herold, Sean G. Rudd, Linda Ljungblad

et al.

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

Published: Jan. 9, 2017

Language: Английский

Citations

124