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

Clonal evolution of acute myeloid leukemia from diagnosis to relapse DOI
Sebastian Vosberg, Philipp A. Greif

Genes Chromosomes and Cancer, Journal Year: 2019, Volume and Issue: 58(12), P. 839 - 849

Published: Sept. 3, 2019

Based on the individual genetic profile, acute myeloid leukemia (AML) patients are classified into clinically meaningful molecular subtypes. However, mutational profile within these groups is highly heterogeneous and multiple AML subclones may exist in a single patient parallel. Distinct alterations of cells be key factors providing fitness to survive this competitive environment. Although majority initially respond induction chemotherapy achieve complete remission, most will eventually relapse. These points toward an evolutionary process transforming treatment-sensitive treatment-resistant cells. As described by Charles Darwin, evolution natural selection individuals that optimally adapted their environment, based random acquisition heritable changes. By changing cell populations able adapt new environment defined treatment, ultimately leading survival regrowth. In review, we summarize current knowledge about clonal AML, describe different models evolution, provide methodological background allows detection patients. During last years, numerous studies have focused delineating patterns associated with relapse, each focusing particular subgroup AML. Finally, review results light Darwinian discuss open questions regarding relapse development.

Language: Английский

Citations

92
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

81
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
Sensing of transposable elements by the antiviral innate immune system DOI Open Access
Ana Gázquez-Gutiérrez, Jeroen Witteveldt, Sara R. Heras

et al.

RNA, Journal Year: 2021, Volume and Issue: 27(7), P. 735 - 752

Published: April 22, 2021

Around half of the genomes in mammals are composed transposable elements (TEs) such as DNA transposons and retrotransposons. Several mechanisms have evolved to prevent their activity detrimental impact insertional mutagenesis. Despite these potentially negative effects, TEs essential drivers evolution, certain settings, beneficial hosts. For instance, rewired antiviral gene regulatory network required for early embryonic development. However, due structural similarities between TE-derived viral nucleic acids, cells can misidentify invading viruses trigger major innate immune pathway, type I interferon (IFN) response. This review will focus on different settings which role TE-mediated IFN activation has been documented, including cancer senescence. Importantly, may also play a causative development complex autoimmune diseases characterized by constitutive activation. All observations suggest presence strong but opposing forces driving coevolution defense. A better biological understanding TE replicative cycle well acid sensing provide insights into how two processes interact help design strategies treat human aberrant expression and/or

Language: Английский

Citations

55
Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55α holoenzymes during mitotic exit DOI Creative Commons
Kerstin Schott, Nina V. Fuchs, Rita Derua

et al.

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: June 4, 2018

Abstract SAMHD1 is a critical restriction factor for HIV-1 in non-cycling cells and its antiviral activity regulated by T592 phosphorylation. Here, we show that dephosphorylation at controlled during the cell cycle, occurring M/G 1 transition proliferating cells. Using several complementary proteomics biochemical approaches, identify phosphatase PP2A-B55α responsible rendering antivirally active. specifically targeted holoenzymes mitotic exit, line with observations key exit mammalian Strikingly, as HeLa or activated primary CD4 + T enter G phase, pronounced reduction of RT products observed upon infection dependent on presence dephosphorylated SAMHD1. Moreover, PP2A controls pT592 level monocyte-derived macrophages (MDMs). Thus, holoenzyme regulator to switch

Language: Английский

Citations

56
SAMHD1 and the innate immune response to cytosolic DNA during DNA replication DOI
Flavie Coquel, Christoph Neumayer, Yea‐Lih Lin

et al.

Current Opinion in Immunology, Journal Year: 2018, Volume and Issue: 56, P. 24 - 30

Published: Oct. 4, 2018

Language: Английский

Citations

51
Ribonucleotides incorporated by the yeast mitochondrial DNA polymerase are not repaired DOI Open Access
Paulina H. Wanrooij, Martin K. M. Engqvist, Josefin M. E. Forslund

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2017, Volume and Issue: 114(47), P. 12466 - 12471

Published: Nov. 6, 2017

Incorporation of ribonucleotides into DNA during genome replication is a significant source genomic instability. The frequency in determined by deoxyribonucleoside triphosphate/ribonucleoside triphosphate (dNTP/rNTP) ratios, the ability polymerases to discriminate against ribonucleotides, and capacity repair mechanisms remove incorporated ribonucleotides. To simultaneously compare how nuclear mitochondrial genomes incorporate we challenged these processes changing balance cellular dNTPs. Using collection yeast strains with altered dNTP pools, discovered an inverse relationship between concentration individual dNTPs amount corresponding DNA, while ribonucleotide pattern was only absence excision repair. Our analysis uncovers major differences two provides concrete evidence that mitochondria lack for removal mtDNA polymerase. Furthermore, as cytosolic pool imbalances were transmitted equally well nucleus mitochondria, our results support view pools frequent exchange.

Language: Английский

Citations

50
SAMHD1 Suppression of Antiviral Immune Responses DOI
Shuliang Chen, Serena Bonifati, Zhihua Qin

et al.

Trends in Microbiology, Journal Year: 2018, Volume and Issue: 27(3), P. 254 - 267

Published: Oct. 15, 2018

Language: Английский

Citations

50
HIV-2/SIV Vpx targets a novel functional domain of STING to selectively inhibit cGAS–STING-mediated NF-κB signalling DOI
Jiaming Su, Yajuan Rui, Meng Lou

et al.

Nature Microbiology, Journal Year: 2019, Volume and Issue: 4(12), P. 2552 - 2564

Published: Oct. 28, 2019

Language: Английский

Citations

48
Aicardi-Goutières syndrome-associated gene SAMHD1 preserves genome integrity by preventing R-loop formation at transcription–replication conflict regions DOI Creative Commons
Kiwon Park, Jeongmin Ryoo,

Heena Jeong

et al.

PLoS Genetics, Journal Year: 2021, Volume and Issue: 17(4), P. e1009523 - e1009523

Published: April 15, 2021

The comorbid association of autoimmune diseases with cancers has been a major obstacle to successful anti-cancer treatment. Cancer survival rate decreases significantly in patients preexisting autoimmunity. However, date, the molecular and cellular profiles such comorbidities are poorly understood. We used Aicardi-Goutières syndrome (AGS) as model disease explored underlying mechanisms genome instability AGS-associated-gene-deficient patient cells. found that R-loops highly enriched at transcription-replication conflict regions fibroblast bearing SAMHD1 mutation, which is AGS-associated-gene mutation most frequently reported tumor malignancies. In SAMHD1-depleted cells, accumulated concomitant activation DNA damage responses. Removal deficiency reduced responses instability. Furthermore, downregulation expression associated various types cancer poor rate. Our findings suggest functions suppressor by resolving R-loops, thus, R-loop may be novel diagnostic markers targets for stratification therapy.

Language: Английский

Citations

37