Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML DOI Creative Commons
Thomas Oellerich,

Constanze Schneider,

Dominique Thomas

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Aug. 2, 2019

Abstract Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms action remain incompletely understood, predictive biomarkers for HMA efficacy lacking. Here, we show that bioactive metabolite triphosphate, but not functions activator substrate triphosphohydrolase SAMHD1 is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis bone marrow specimens from AML patients at diagnosis revealed expression leukemic cells inversely correlates with clinical response decitabine, azacytidine. ablation increases antileukemic activity cell lines, primary blasts, xenograft models. acquire resistance partly by up-regulation. Together, our data suggest a biomarker stratified use hypomethylating potential target decitabine-resistant leukemia.

Language: Английский

GTP activator and dNTP substrates of HIV-1 restriction factor SAMHD1 generate a long-lived activated state DOI Open Access

Erik C Hansen,

Kyle J. Seamon,

Shannen L. Cravens

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2014, Volume and Issue: 111(18)

Published: April 21, 2014

Significance The degradative dNTP triphosphohydrolase activity of the sterile α-motif/histidine-aspartate domain-containing protein 1 (SAMHD1) enzyme helps maintain optimal balances for DNA replication and also serves as an HIV-1 restriction factor in resting CD4 + target cells HIV by depleting substrates reverse transcriptase. This study shows that full activation SAMHD1 involves ordered binding GTP substrate dNTPs to activator sites on enzyme, leading assembly tetramer active form. After is activated, it no longer communicates with free nucleotides, which contributes efficient depletion pools T cells.

Language: Английский

Citations

101
From APOBEC to ZAP: Diverse mechanisms used by cellular restriction factors to inhibit virus infections DOI Creative Commons
Mahesh Chemudupati, Adam D. Kenney, Serena Bonifati

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Journal Year: 2018, Volume and Issue: 1866(3), P. 382 - 394

Published: Oct. 2, 2018

Language: Английский

Citations

92
SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity DOI
Jenna M. Antonucci,

Corine St. Gelais,

Suresh de Silva

et al.

Nature Medicine, Journal Year: 2016, Volume and Issue: 22(10), P. 1072 - 1074

Published: Oct. 1, 2016

Language: Английский

Citations

88
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
Deoxyribonucleotides as genetic and metabolic regulators DOI

Christopher K. Mathews

The FASEB Journal, Journal Year: 2014, Volume and Issue: 28(9), P. 3832 - 3840

Published: June 13, 2014

For >35 yr, we have known that the accuracy of DNA replication is controlled in large part by relative concentrations 4 canonical deoxyribonucleoside 5'-triphosphates (dNTPs) at replisome. Since this field was last reviewed, ∼8 yr ago, there has been increased understanding mutagenic pathways as they occur living cells. At same time, aspects deoxyribonucleotide metabolism shown to be critically involved processes diverse cell cycle control, protooncogene expression, cellular defense against HIV infection, rate telomere length and mitochondrial function. Evidence supports a relationship between dNTP pools microsatellite repeat instability. Relationships synthesis breakdown controlling steady-state become better defined. In addition, new experimental approaches allowed definitive analysis mutational induced pool abnormalities, both Escherichia coli yeast. Finally, ribonucleoside triphosphate (rNTP) critical determinants fidelity. These developments are discussed review article.

Language: Английский

Citations

91
CyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain DOI Creative Commons

Junpeng Yan,

Caili Hao,

Maria DeLucia

et al.

Journal of Biological Chemistry, Journal Year: 2015, Volume and Issue: 290(21), P. 13279 - 13292

Published: April 7, 2015

Language: Английский

Citations

90
SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction DOI
Ester Ballana, José A. Esté

Trends in Microbiology, Journal Year: 2015, Volume and Issue: 23(11), P. 680 - 692

Published: Oct. 3, 2015

Language: Английский

Citations

83
Impaired dNTPase Activity of SAMHD1 by Phosphomimetic Mutation of Thr-592 DOI Creative Commons

Chenxiang Tang,

Xiaoyun Ji, Li Wu

et al.

Journal of Biological Chemistry, Journal Year: 2015, Volume and Issue: 290(44), P. 26352 - 26359

Published: Aug. 21, 2015

Language: Английский

Citations

81
SAMHD1 specifically restricts retroviruses through its RNase activity DOI Creative Commons
Jongsu Choi, Jeongmin Ryoo, Changhoon Oh

et al.

Retrovirology, Journal Year: 2015, Volume and Issue: 12(1)

Published: June 2, 2015

Human SAMHD1 possesses dual enzymatic functions. It acts as both a dGTP-dependent triphosphohydrolase and an exoribonuclease. The dNTPase function depletes the cellular dNTP pool, which is required for retroviral reverse transcription in differentiated myeloid cells resting CD4(+) T cells; thus this activity mainly plays role SAMHD1-mediated restriction. However, recent study demonstrated that directly targets HIV-1 genomic RNA via its RNase activity, (rather than activity) sufficient While potent target during viral infection, specificity of infection by other viruses unclear.The results present showed specifically degrades monocyte-derived macrophage-like primary macrophages. Consistent with this, selectively restricted replication, but did not affect replication common non-retro genome viruses, suggesting RNase-mediated antiviral limited to retroviruses. In addition, neither inhibiting treatment several transcriptase inhibitors nor transcriptase-defective altered levels after challenge, indicating retrovirus-specific dependent on processes associated transcription.The presented herein suggest control retroviruses, viruses.

Language: Английский

Citations

75
SAMHD1 controls innate immunity by regulating condensation of immunogenic self RNA DOI Creative Commons
Shovamayee Maharana, Stefanie Kretschmer,

Susan Hunger

et al.

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(19), P. 3712 - 3728.e10

Published: Sept. 22, 2022

Language: Английский

Citations

34