Affinage

DUT

Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial · UniProt P33316

Length
252 aa
Mass
26.6 kDa
Annotated
2026-06-09
100 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DUT encodes dUTPase, an essential nucleotide-metabolic enzyme that hydrolyzes dUTP to dUMP and pyrophosphate, simultaneously cleansing the cellular dUTP pool to block uracil misincorporation into DNA and supplying dUMP for thymidylate biosynthesis (PMID:15322254, PMID:16617146). The enzyme is a symmetrical homotrimer built on a jelly-roll fold lacking the classical nucleotide-binding domain, with active sites formed at the interfaces between adjacent subunits and a C-terminal arm that swaps between subunits to organize the trimer and closes over the active site during catalysis (PMID:1311056, PMID:8646539, PMID:19302784, PMID:14724274). Catalysis proceeds through Mg²⁺-assisted, in-line nucleophilic attack on the α-phosphate by a water molecule activated by an active-site general base whose pKa is raised by a transiently ordered C-terminal loop, with aromatic stacking of the uracil ring stabilizing the transition state; the multistep cycle (binding, isomerization, rate-limiting hydrolysis, product release) releases protons concomitant with the chemical step (PMID:8798636, PMID:15276840, PMID:17848562, PMID:20601405). Human DUT produces a nuclear isoform (DUT-N) and a mitochondrial isoform (DUT-M) via alternative 5' exon usage, the latter carrying a cleavable targeting presequence; DUT-N nuclear import depends on a basic NLS (K14/R15/R17) and is controlled by cell-cycle-dependent phosphorylation at Ser11, which during M phase weakens importin-α binding and excludes the enzyme from the nucleus (PMID:9228092, PMID:24311590, PMID:12799180, PMID:8389461). The downstream importance of this pool control is established genetically: dUTPase loss elevates genomic uracil and, through uracil-DNA glycosylase-mediated excision, generates AP sites and double-strand breaks that demand recombinational repair, while restoring dUTPase activity abolishes dUTP-driven genome instability (PMID:16617146, PMID:14982624, PMID:27452458). DUT is essential for mammalian embryonic development (dut⁻/⁻ mice die after implantation) and for pancreatic β-cell survival, and a DUT point mutation causes a monogenic syndrome of early-onset diabetes and bone marrow failure (PMID:30987342, PMID:28073829).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1992 High

    Established the architecture of dUTPase, showing it is a symmetrical homotrimer with a jelly-roll fold and inter-subunit active sites rather than a conventional nucleotide-binding enzyme.

    Evidence 1.9 Å X-ray crystal structure of E. coli dUTPase

    PMID:1311056

    Open questions at the time
    • No bound substrate/metal to define catalytic geometry
    • Eukaryotic enzyme architecture not yet addressed
  2. 1996 High

    Defined how substrate is recognized and how the catalytic chemistry works, locating the uracil/deoxyribose contacts and assigning Mg²⁺ and a shielded water to rate-limiting α-phosphate hydrolysis.

    Evidence Co-crystal with dUDP plus comprehensive steady-state and pre-steady-state kinetics of E. coli enzyme

    PMID:8646539 PMID:8798636

    Open questions at the time
    • General base not yet identified by residue
    • Conformational dynamics during the cycle not resolved
  3. 1997 High

    Resolved how a single gene serves two compartments, showing alternative 5' exon usage generates a cell-cycle-regulated nuclear isoform and a constitutive mitochondrial isoform with a cleavable presequence.

    Evidence cDNA cloning, mitochondrial import assay, IEF, genomic sequencing of human DUT

    PMID:9228092

    Open questions at the time
    • Functional requirement for the mitochondrial pool not tested
    • Import/regulatory machinery not identified
  4. 2004 High

    Provided the atomic mechanism of catalysis and revealed eukaryote-specific conformational behavior, defining Mg²⁺ tridentate coordination, a general-base aspartate shielded by an ordered C-terminal loop, and product-induced active-site closure.

    Evidence 1.3 Å M. tuberculosis structure with Mg²⁺ and imido-dUTP; Drosophila crystallography with proteolysis/calorimetry; yeast and E. coli epistasis defining the uracil-excision pathway

    PMID:14724274 PMID:14982624 PMID:15276840 PMID:16617146

    Open questions at the time
    • Human-specific transition-state details not yet shown
    • Quantitative contribution of C-terminal arm dynamics unresolved
  5. 2004 High

    Demonstrated the cellular consequence of pool control, showing dUTPase suppression expands dUTP pools, causes uracil-misincorporation DSBs, and sensitizes cancer cells to thymidylate synthase-directed therapy.

    Evidence siRNA knockdown in SW620/MCF-7 with nucleotide pool, DSB, and clonogenic/FUdR sensitivity readouts

    PMID:15322254

    Open questions at the time
    • Did not separate nuclear vs mitochondrial isoform contributions
    • In vivo therapeutic relevance not tested
  6. 2007 High

    Dissected the human catalytic cycle into discrete kinetic steps, identifying isomerization to a competent conformation and a rate-limiting chemical step coupled to proton release.

    Evidence Pre-steady-state stopped-flow/quenched-flow with an engineered active-site tryptophan sensor in human dUTPase

    PMID:17848562

    Open questions at the time
    • Structural state of the isomerized intermediate not captured
    • Regulation of cycle in cellular context unaddressed
  7. 2009 High

    Explained the structural basis of oligomerization, showing C-terminal β-strand swapping between subunits is required for trimer assembly and that a hinge proline stabilizes the fold.

    Evidence Drosophila crystal structure, SAXS, C-terminal truncations and hinge-proline mutagenesis across species

    PMID:19302784

    Open questions at the time
    • Functional consequence of monomerization in cells not tested
  8. 2010 High

    Identified a remote catalytic enhancer, showing π-π stacking on the uracil ring stabilizes an associative transition state and accelerates α-phosphate hydrolysis.

    Evidence Combined crystallography, kinetics, spectroscopy, thermodynamics and mutagenesis

    PMID:20601405

    Open questions at the time
    • Magnitude of contribution across orthologs not generalized
  9. 2013 High

    Defined the regulatory logic of nuclear access, showing M-phase phosphorylation at Ser11 weakens importin-α binding to exclude dUTPase from the nucleus, integrating localization with the cell cycle.

    Evidence Importin-α/NLS-peptide crystal structures, ITC, and localization of phosphomimetic/phosphoablative mutants; earlier 2D-PAGE showing cell-cycle-dependent phosphorylation in T cells; prior GFP-mapping of the K14R15R17 NLS

    PMID:12799180 PMID:24311590 PMID:8389461

    Open questions at the time
    • Identity of the M-phase kinase not established
    • The 2003 GFP system did not detect a phospho-effect, leaving context dependence unresolved
  10. 2016 Medium

    Placed dUTPase as a direct buffer of replication-stress-driven instability, showing its activity abolishes the genome instability caused by ribonucleotide reductase R2 overexpression.

    Evidence R2 and dUTPase overexpression with replication-fork, genomic uracil, and fragile-site assays

    PMID:27452458

    Open questions at the time
    • Overexpression-based epistasis only
    • Endogenous-level relevance not established
  11. 2017 Medium

    Established mammalian essentiality and disease relevance, showing DUT loss is embryonic lethal, is required for β-cell survival, and that a point mutation causes a diabetes/bone-marrow-failure syndrome; parallel mycobacterial work decoupled DNA-uracilation prevention from dNTP-balance control.

    Evidence CRISPR dut⁻/⁻ mouse embryos; whole-exome sequencing plus β-cell siRNA/apoptosis assays; genetic separation of Dut vs Dcd:dut in M. smegmatis

    PMID:28073829 PMID:28729658 PMID:30987342

    Open questions at the time
    • Mechanism linking DUT loss to β-cell-specific apoptosis not fully defined
    • Whether embryonic lethality reflects pool cleansing vs an additional function unresolved
  12. 2018 Medium

    Characterized a protein-level inhibitory interaction, showing the staphylococcal repressor Stl binds human dUTPase via its active-site-forming segments, inhibiting the enzyme and dissociating the Stl DNA-binding dimer.

    Evidence SAXS, HDX-MS, enzymatic and DNA-binding assays of the human dUTPase–Stl complex

    PMID:29531348

    Open questions at the time
    • Physiological relevance of the interaction to host biology unclear
    • High-resolution structure of the complex not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The nature of the essential function beyond dUTP-pool cleansing, implied by lethality persisting in metabolically compensated backgrounds, remains undefined.
  • No molecular identity for a 'moonlighting' essential function
  • Distinct roles of nuclear vs mitochondrial isoforms in vivo not separated
  • M-phase kinase for Ser11 not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0140098 catalytic activity, acting on RNA 3
Localization
GO:0005634 nucleus 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-73894 DNA Repair 3
Partners
KPNA2STL
Complex memberships
dUTPase homotrimer

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 Crystal structure of E. coli dUTPase determined at 1.9 Å resolution, revealing the enzyme is a symmetrical homotrimer with a jelly-roll fold lacking the classical nucleotide-binding domain; conserved sequence elements are located at subunit interfaces, suggesting inter-subunit interactions contribute to catalysis. X-ray crystallography Nature High 1311056
1996 Crystal structure of E. coli dUTPase in complex with substrate analogue dUDP at atomic resolution shows three dUDP molecules bound symmetrically per trimer in shallow clefts between adjacent subunits, with conserved residues contacting the uracil ring and deoxypentose; positions of phosphate groups and adjacent water molecules inform the catalytic mechanism. X-ray crystallography with bound inhibitor/substrate analogue Nature structural biology High 8646539
1996 Kinetic characterization of E. coli dUTPase showed: strict specificity for dUTP (dCTP hydrolyzed ~10^5 times less efficiently); kcat 6–9 s⁻¹; Km ~10⁻⁷ M near neutral pH; Mg²⁺ enhances dUTP binding ~100-fold; only one enantiomer of a thio-dUTP analogue is hydrolyzed; protons released concertedly after the rate-limiting step; proposed mechanism involves Mg²⁺ binding at α-phosphate with rate-limiting hydrolysis by a shielded water molecule. Steady-state and pre-steady-state enzymology, pH-rate studies, isotope effects, substrate stereochemistry The Journal of biological chemistry High 8798636
1997 Human DUT gene encodes both nuclear (DUT-N) and mitochondrial (DUT-M) isoforms via alternative 5' exon usage from the same gene. DUT-M contains a 69-residue mitochondrial targeting presequence that is cleaved upon import, producing a 23 kDa mature protein. DUT-N is cell-cycle-regulated (elevated during DNA replication), whereas DUT-M is constitutively expressed. cDNA cloning, in vitro transcription/translation, mitochondrial import assay, Northern/Western blot, isoelectric focusing, genomic DNA sequencing The Journal of biological chemistry High 9228092
2004 Crystal structure of Mycobacterium tuberculosis dUTPase at 1.3 Å in complex with Mg²⁺ and non-hydrolyzable substrate analogue α,β-imido-dUTP reveals that Mg²⁺ coordinates α-, β-, and γ-phosphate groups in tridentate geometry, stabilising the α-phosphorus for in-line nucleophilic attack; a transiently ordered C-terminal loop shields the general-base Asp83 from solvent, raising its pKa to activate a water molecule for nucleophilic attack. X-ray crystallography with Mg²⁺ and substrate analogue Journal of molecular biology High 15276840
2007 Pre-steady-state and steady-state kinetics of human dUTPase (using an engineered tryptophan fluorescence sensor in the active site) revealed the catalytic cycle consists of four steps: (i) fast substrate binding, (ii) isomerization to catalytically competent conformation, (iii) rate-limiting hydrolysis (chemical step), and (iv) rapid non-ordered product release. Proton release is concomitant with the rate-limiting hydrolysis step. Pre-steady-state kinetics (stopped-flow fluorescence), quenched-flow with γ-³²P-dUTP, indicator-based rapid kinetic assays, site-directed mutagenesis (Trp sensor) The Journal of biological chemistry High 17848562
2013 Phosphorylation of human nuclear dUTPase at Ser11 (adjacent to its NLS) occurs specifically during M phase of the cell cycle, mediated by cell-cycle kinase activity, and abolishes nuclear import by significantly weakening interaction with importin-α. Crystal structures of importin-α bound to wild-type and phosphomimetic (S11E) dUTPase NLS peptides provide structural explanation for this regulation. X-ray crystallography, isothermal titration calorimetry, cell biological localization studies with phosphomimetic/phosphoablative mutants, NLS-importin-α binding assays Acta crystallographica Section D High 24311590
2003 The N-terminal 23 amino acids of human DUT-N are required (but not sufficient) for nuclear localization; a cluster of basic residues K14R15R17 constitutes a functional nuclear localization signal whose mutation completely abolishes nuclear import. Ser11 phosphorylation (noted in this paper) does not affect DUT-N nuclear localization in the GFP-fusion system used here. GFP fusion constructs, deletion analysis, site-directed mutagenesis, fluorescence microscopy Experimental cell research Medium 12799180
2017 CRISPR/Cas9 knock-out of dUTPase in mice is embryonic lethal: dut⁻/⁻ embryos reach the blastocyst stage but die shortly after implantation, with perturbed growth of both inner cell mass and trophectoderm; heterozygous dut⁺/⁻ animals are viable with reduced dUTPase levels. CRISPR/Cas9 gene editing in mice, embryo analysis, blastocyst staging Biomolecules High 30987342
2017 DUT mutation (p.Y54C in DUT-N / p.Y142C in DUT-M) identified as the cause of a monogenic syndrome with early-onset diabetes and bone marrow failure. DUT silencing in human and rat pancreatic β-cells causes apoptosis via the intrinsic cell death pathway, demonstrating that DUT is required for β-cell survival. Whole-exome sequencing (patient genetics), siRNA knockdown in pancreatic β-cells, apoptosis assays Diabetes Medium 28073829
1993 Human dUTPase (nuclear isoform) is phosphorylated in a cell-cycle-dependent manner in mature T cells; phosphorylated and unphosphorylated forms accumulate in a proliferation-dependent manner, whereas immature thymocytes constitutively express both forms independent of cell cycle. 2D PAGE, cDNA cloning from partial protein sequence, Western blot Proceedings of the National Academy of Sciences Medium 8389461
2004 siRNA-mediated suppression of dUTPase in human cancer cell lines SW620 and MCF-7 significantly expands dUTP pools following thymidylate synthase inhibition, enhances DNA double-strand break formation, and decreases FUdR IC₅₀ ~75-fold and ~6-fold respectively, demonstrating that dUTPase controls cellular dUTP levels and protects cells from uracil-misincorporation-induced DNA damage. siRNA knockdown, nucleotide pool measurements, clonogenic survival assay, DNA damage assays (DSBs) Molecular pharmacology High 15322254
2004 dUTPase activity loss in S. cerevisiae (dut1-1 mutant with G82S substitution near active site) causes growth delay, cell cycle abnormalities, and a strong spontaneous mutator phenotype. All phenotypes are suppressed by inactivation of uracil-DNA glycosylase (Ung1), establishing that dUTPase phenotypes arise from dUMP incorporation into DNA followed by uracil excision creating AP sites. Yeast genetics (viable dut1-1 allele), double-mutant epistasis (dut1-1 ung1), mutation spectrum analysis, cell cycle analysis Nucleic acids research High 16617146
2004 E. coli dut recA double mutants are synthetically lethal, and chromosomal fragmentation (double-strand DNA breaks) is detected in dut rec mutants. The synthetic lethality and fragmentation are suppressed by inactivating uracil-DNA glycosylase (ung) or dCTP deaminase (dcd), showing dUTPase loss causes DSBs via a uracil-excision intermediate requiring RecBC-RuvABC recombinational repair for viability. Genetic epistasis (synthetic lethality screen), pulsed-field gel electrophoresis to detect DSBs, multiple suppressor combinations Molecular microbiology High 14982624
2010 A conserved aromatic stacking interaction between dUTPase and the uracil moiety of its substrate contributes to stabilisation of an associative-type transition state during α-phosphate hydrolysis; the π-π interaction remote from the hydrolysis site accelerates catalysis. Crystallographic, kinetic, spectroscopic, and thermodynamic data support this mechanism. X-ray crystallography, enzyme kinetics, optical spectroscopy, thermodynamics calculations, site-directed mutagenesis Nucleic acids research High 20601405
2009 C-terminal β-strand swapping between subunits is critical for dUTPase homotrimer organisation; truncation of the C-terminus before the swapping arm prevents trimer formation in human dUTPase. Mutations of a conserved hinge proline destabilise human and E. coli dUTPases without preventing trimeric organisation. X-ray crystallography (Drosophila dUTPase dimer crystal), small-angle X-ray scattering, site-directed mutagenesis, C-terminal truncations FEBS letters High 19302784
2016 Overexpression of ribonucleotide reductase subunit R2 in non-tumorigenic cells causes genome instability (replication fork alterations, elevated genomic uracil, fragile-site breaks) that is fully abolished by dUTPase overexpression, demonstrating that dUTPase activity directly controls dUTP-driven genome instability downstream of RNR. Stable R2 overexpression, dUTPase overexpression, replication fork assays, genomic uracil measurement, fragile-site analysis Cell reports Medium 27452458
2013 HSV-1 protein kinase Us3 phosphorylates viral dUTPase (vdUTPase) at Ser187 in infected cells; this phosphorylation is required for optimal dUTPase enzymatic activity and promotes HSV-1 replication in neuronal (SK-N-SH) but not Vero/HEp-2 cells. Phosphomimetic substitution at Ser187 rescues both enzymatic activity and viral replication defects caused by kinase-dead Us3. Large-scale phosphoproteomics (TiO₂/MS), in vitro kinase assay, phosphate-affinity PAGE, site-directed mutagenesis (S187A phosphomimetic), viral replication assays Journal of virology High 24173231
1988 Chromosomal dut null mutations are lethal in E. coli even in the presence of compensatory metabolic mutations (dcd, cdd, ung, deoA, sulA, alone or combined), suggesting dUTPase has an essential function beyond its nucleotide pool-cleansing role. Allelic exchange, generalized transduction, genetic complementation in multiple mutant backgrounds Journal of bacteriology Medium 2830228
2018 The Staphylococcal repressor Stl forms a stable complex with human dUTPase trimers, inhibiting dUTPase enzymatic activity; active-site-forming segments of dUTPase are directly involved in the Stl interaction (identified by HDX-MS). Complex formation dissociates the Stl homodimer, abolishing Stl's DNA-binding ability. SAXS, hydrogen-deuterium exchange mass spectrometry (HDX-MS), functional enzymatic assays, DNA-binding assays Scientific reports Medium 29531348
2004 Eukaryotic (Drosophila) dUTPase, unlike the bacterial enzyme, shows Mg²⁺-dependent conformational changes, and product dUMP induces protection against proteolysis (closed active-site conformation); the C-terminal arm is critical for activity; a stable but inactive homotrimeric core domain is generated by limited trypsinolysis. Crystallographic analysis reveals a stable monomer in the crystal phase (distinct from trimeric bacterial enzyme). X-ray crystallography, kinetic analysis, limited proteolysis, fluorescence spectroscopy, differential scanning calorimetry The Journal of biological chemistry High 14724274
2017 In a mycobacterial model encoding both Dut (monofunctional dUTPase) and Dcd:dut (bifunctional dCTP deaminase/dUTPase), Dut specifically prevents DNA uracilation (dut mutant increases genomic uracil and mutation rate) without affecting dTTP/dCTP balance, while Dcd:dut controls dNTP balance without affecting DNA uracil content. The two enzyme activities are functionally decoupled. Genetic knock-out/knock-down in Mycobacterium smegmatis, genomic uracil measurement, dNTP pool analysis, mutation rate assays Scientific reports High 28729658
2004 Drosophila dUTPase is expressed as two isoforms during development (identified at mRNA and protein levels); expression decreases drastically at the protein level during larval stages despite constitutive mRNA levels, indicating multilevel regulation; macromolecular protein partners of dUTPase were verified by independent approaches, and a putative nuclear localization signal is present in one isoform, though subcellular localisation is not strictly determined by the NLS alone. Western blot, Northern blot, immunohistochemistry, co-purification approaches for interacting partners The Journal of biological chemistry Low 14996835

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1988 Lethality of a dut (deoxyuridine triphosphatase) mutation in Escherichia coli. Journal of bacteriology 182 2830228
1992 Distinct subsets of retroviruses encode dUTPase. Journal of virology 144 1310783
1992 Crystal structure of a dUTPase. Nature 142 1311056
2009 The EBV-encoded dUTPase activates NF-kappa B through the TLR2 and MyD88-dependent signaling pathway. Journal of immunology (Baltimore, Md. : 1950) 135 19124728
2002 Roles of uracil-DNA glycosylase and dUTPase in virus replication. The Journal of general virology 107 12237414
1996 Crystal structure of the Escherichia coli dUTPase in complex with a substrate analogue (dUDP). Nature structural biology 98 8646539
1993 Characterization of equine infectious anemia virus dUTPase: growth properties of a dUTPase-deficient mutant. Journal of virology 97 8386267
2001 The role of dUTPase and uracil-DNA repair in cancer chemotherapy. Current protein & peptide science 96 12374095
1995 Replication in vitro and in vivo of an equine infectious anemia virus mutant deficient in dUTPase activity. Journal of virology 93 7707512
1999 Evolution and horizontal transfer of dUTPase-encoding genes in viruses and their hosts. Journal of virology 91 10438861
1996 Kinetic characterization of dUTPase from Escherichia coli. The Journal of biological chemistry 87 8798636
2006 EBV-encoded dUTPase induces immune dysregulation: Implications for the pathophysiology of EBV-associated disease. Virology 86 16321417
1997 The human dUTPase gene encodes both nuclear and mitochondrial isoforms. Differential expression of the isoforms and characterization of a cDNA encoding the mitochondrial species. The Journal of biological chemistry 83 9228092
2013 Epstein-Barr virus encoded dUTPase containing exosomes modulate innate and adaptive immune responses in human dendritic cells and peripheral blood mononuclear cells. PloS one 79 23894549
2004 Crystal structure of the Mycobacterium tuberculosis dUTPase: insights into the catalytic mechanism. Journal of molecular biology 78 15276840
1999 African swine fever virus dUTPase is a highly specific enzyme required for efficient replication in swine macrophages. Journal of virology 70 10515998
1997 dUTPase-minus caprine arthritis-encephalitis virus is attenuated for pathogenesis and accumulates G-to-A substitutions. Journal of virology 68 9151845
2004 Chromosomal fragmentation in dUTPase-deficient mutants of Escherichia coli and its recombinational repair. Molecular microbiology 65 14982624
2004 Small interfering RNA-mediated suppression of dUTPase sensitizes cancer cell lines to thymidylate synthase inhibition. Molecular pharmacology 64 15322254
2017 Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I Interferon Receptor 1 and Antagonizes the Alpha Interferon Response. Journal of virology 62 28794045
2005 New genes from old: redeployment of dUTPase by herpesviruses. Journal of virology 61 16188990
2004 The crystal structure of Trypanosoma cruzi dUTPase reveals a novel dUTP/dUDP binding fold. Structure (London, England : 1993) 60 14725764
2002 Archaeal dUTPase enhances PCR amplifications with archaeal DNA polymerases by preventing dUTP incorporation. Proceedings of the National Academy of Sciences of the United States of America 60 11782527
2015 Exceptional adsorption-induced cluster and network deformation in the flexible metal-organic framework DUT-8(Ni) observed by in situ X-ray diffraction and EXAFS. Physical chemistry chemical physics : PCCP 58 26079102
2008 Active site of mycobacterial dUTPase: structural characteristics and a built-in sensor. Biochemical and biophysical research communications 58 18519027
2007 Kinetic mechanism of human dUTPase, an essential nucleotide pyrophosphatase enzyme. The Journal of biological chemistry 58 17848562
2006 dUTPase activity is critical to maintain genetic stability in Saccharomyces cerevisiae. Nucleic acids research 56 16617146
1997 Disruption of the varicella-zoster virus dUTPase and the adjacent ORF9A gene results in impaired growth and reduced syncytia formation in vitro. Virology 54 9268149
1983 Nucleotide sequence of the structural gene for dUTPase of Escherichia coli K-12. The EMBO journal 54 6139280
1993 Maturation stage and proliferation-dependent expression of dUTPase in human T cells. Proceedings of the National Academy of Sciences of the United States of America 53 8389461
2019 Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Clinical therapeutics 50 31040055
1992 A meristem-related gene from tomato encodes a dUTPase: analysis of expression in vegetative and floral meristems. The Plant cell 50 1321683
1986 Isolation and characterisation of herpes simplex virus type 1 mutants which fail to induce dUTPase activity. Virology 50 3002029
2011 A human endogenous retrovirus K dUTPase triggers a TH1, TH17 cytokine response: does it have a role in psoriasis? The Journal of investigative dermatology 49 21776007
2011 The anti-interferon activity of conserved viral dUTPase ORF54 is essential for an effective MHV-68 infection. PLoS pathogens 48 21998588
2011 Inhibition of dUTPase induces synthetic lethality with thymidylate synthase-targeted therapies in non-small cell lung cancer. Molecular cancer therapeutics 48 22172489
2006 Quantitative determination of uracil residues in Escherichia coli DNA: Contribution of ung, dug, and dut genes to uracil avoidance. DNA repair 48 16908222
2012 Kaposi's sarcoma-associated herpesvirus ORF54/dUTPase downregulates a ligand for the NK activating receptor NKp44. Journal of virology 47 22674989
2007 Epstein-Barr virus-encoded dUTPase enhances proinflammatory cytokine production by macrophages in contact with endothelial cells: evidence for depression-induced atherosclerotic risk. Brain, behavior, and immunity 47 17845840
1993 Identification and deletion mutagenesis of the bovine herpesvirus 1 dUTPase gene and a gene homologous to herpes simplex virus UL49.5. Virology 47 8391186
2015 dUTPase: the frequently overlooked enzyme encoded by many retroviruses. Retrovirology 46 26259899
2012 The dUTPase enzyme is essential in Mycobacterium smegmatis. PloS one 45 22655049
2010 Aromatic stacking between nucleobase and enzyme promotes phosphate ester hydrolysis in dUTPase. Nucleic acids research 45 20601405
1993 Vaccinia virus encodes a functional dUTPase. Virology 45 8393252
2002 dUTPase and uracil-DNA glycosylase are central modulators of antifolate toxicity in Saccharomyces cerevisiae. Cancer research 44 12208740
2013 Herpes simplex virus 1 protein kinase Us3 phosphorylates viral dUTPase and regulates its catalytic activity in infected cells. Journal of virology 42 24173231
2006 Flexible segments modulate co-folding of dUTPase and nucleocapsid proteins. Nucleic acids research 42 17169987
2000 Deoxyuridine triphosphatase (dUTPase) expression and sensitivity to the thymidylate synthase (TS) inhibitor ZD9331. British journal of cancer 42 10952785
1994 The protein p30, encoded at the gag-pro junction of mouse mammary tumor virus, is a dUTPase fused with a nucleocapsid protein. Virology 40 8091672
1992 dcd (dCTP deaminase) gene of Escherichia coli: mapping, cloning, sequencing, and identification as a locus of suppressors of lethal dut (dUTPase) mutations. Journal of bacteriology 40 1324907
2004 Altered active site flexibility and a structural metal-binding site in eukaryotic dUTPase: kinetic characterization, folding, and crystallographic studies of the homotrimeric Drosophila enzyme. The Journal of biological chemistry 39 14724274
2000 The non-essential UL50 gene of avian infectious laryngotracheitis virus encodes a functional dUTPase which is not a virulence factor. The Journal of general virology 39 10675400
2001 Kinetic properties and inhibition of the dimeric dUTPase-dUDPase from Leishmania major. Protein science : a publication of the Protein Society 36 11420444
2021 Monocyte-released HERV-K dUTPase engages TLR4 and MCAM causing endothelial mesenchymal transition. JCI insight 35 34185707
2008 Depletion of dimeric all-alpha dUTPase induces DNA strand breaks and impairs cell cycle progression in Trypanosoma brucei. The international journal of biochemistry & cell biology 35 18656547
2006 Characterization of an early gene encoding for dUTPase in Rana grylio virus. Virus research 35 16989917
2004 Developmental regulation of dUTPase in Drosophila melanogaster. The Journal of biological chemistry 35 14996835
1999 Structure/function analysis of a dUTPase: catalytic mechanism of a potential chemotherapeutic target. Journal of molecular biology 35 10329142
1994 Expression and purification of the mouse mammary tumor virus gag-pro transframe protein p30 and characterization of its dUTPase activity. Journal of virology 35 8139016
1990 Cell cycle- and differentiation stage-dependent variation of dUTPase activity in higher plant cells. Experimental cell research 34 2153555
2017 dUTPase inhibition augments replication defects of 5-Fluorouracil. Oncotarget 33 28423595
2013 Phosphorylation adjacent to the nuclear localization signal of human dUTPase abolishes nuclear import: structural and mechanistic insights. Acta crystallographica. Section D, Biological crystallography 33 24311590
1998 Biochemical and phylogenetic characterization of the dUTPase from the archaeal virus SIRV. The Journal of biological chemistry 33 9497317
1996 Identification and characterization of pseudorabies virus dUTPase. Journal of virology 33 8551588
2019 Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target. mBio 32 31662460
2008 Methylene substitution at the alpha-beta bridging position within the phosphate chain of dUDP profoundly perturbs ligand accommodation into the dUTPase active site. Proteins 30 17932923
2007 Mechanism of dTTP inhibition of the bifunctional dCTP deaminase:dUTPase encoded by Mycobacterium tuberculosis. Journal of molecular biology 30 18164314
1997 Study of immunogenicity and virulence of bovine herpesvirus 1 mutants deficient in the UL49 homolog, UL49.5 homolog and dUTPase genes in cattle. Vaccine 30 9269047
1993 dUTPase from herpes simplex virus type 1; purification from infected green monkey kidney (Vero) cells and from an overproducing Escherichia coli strain. Protein expression and purification 29 8386036
2013 Phosphorylation of a herpes simplex virus 1 dUTPase by a viral protein kinase, Us3, dictates viral pathogenicity in the central nervous system but not at the periphery. Journal of virology 28 24352467
2008 Synthetic lethality with the dut defect in Escherichia coli reveals layers of DNA damage of increasing complexity due to uracil incorporation. Journal of bacteriology 28 18586941
2016 Life without dUTPase. Frontiers in microbiology 27 27933035
2001 Evolution of the DUT gene: horizontal transfer between host and pathogen in all three domains of life. Current protein & peptide science 27 12369928
2020 dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA-repair-defective human cancer cells. Cancer science 26 33140501
1998 Mechanism and pharmacological specificity of dUTPase-mediated protection from DNA damage and cytotoxicity in human tumor cells. Cancer chemotherapy and pharmacology 26 9771948
1997 Characterization and mutational studies of equine infectious anemia virus dUTPase. Biochimica et biophysica acta 26 9187238
1996 Synthesis of 2'-deoxyuridine 5'-(alpha,beta-imido) triphosphate: a substrate analogue and potent inhibitor of dUTPase. Bioorganic & medicinal chemistry 26 8735843
2016 The nucleotidohydrolases DCTPP1 and dUTPase are involved in the cellular response to decitabine. The Biochemical journal 25 27325794
2003 Structural basis for recognition and catalysis by the bifunctional dCTP deaminase and dUTPase from Methanococcus jannaschii. Journal of molecular biology 25 12909016
2001 Evolution of the dUTPase gene of mammalian and avian herpesviruses. Current protein & peptide science 25 12369929
2018 TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy. Molecular cancer therapeutics 24 29748212
2016 The Impact of dUTPase on Ribonucleotide Reductase-Induced Genome Instability in Cancer Cells. Cell reports 24 27452458
2013 Structure and enzymatic mechanism of a moonlighting dUTPase. Acta crystallographica. Section D, Biological crystallography 23 24311572
2011 β-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase. Bioorganic & medicinal chemistry 23 21411327
2009 Molecular shape and prominent role of beta-strand swapping in organization of dUTPase oligomers. FEBS letters 23 19302784
2008 Identification and characterization of duck enteritis virus dUTPase gene. Avian diseases 23 18646465
2008 Higher expression of deoxyuridine triphosphatase (dUTPase) may predict the metastasis potential of colorectal cancer. Journal of clinical pathology 23 19052026
2004 Evidence that the human cytomegalovirus 46-kDa UL72 protein is not an active dUTPase but a late protein dispensable for replication in fibroblasts. Virology 23 15246266
2017 Differential control of dNTP biosynthesis and genome integrity maintenance by the dUTPase superfamily enzymes. Scientific reports 22 28729658
1997 Attenuation of dUTPase-deficient pseudorabies virus for the natural host. Veterinary microbiology 22 9228681
1997 A consensus sequence for a functional human endogenous retrovirus K (HERV-K) dUTPase. Biochemistry and cell biology = Biochimie et biologie cellulaire 22 9250362
1996 Cloning and expression of the Epstein-Barr virus-encoded dUTPase: patients with acute, reactivated or chronic virus infection develop antibodies against the enzyme. The Journal of general virology 22 8922474
1995 dUTPase from the retrovirus equine infectious anemia virus: high-level expression in Escherichia coli and purification. Protein expression and purification 22 7663176
2018 Structural model of human dUTPase in complex with a novel proteinaceous inhibitor. Scientific reports 21 29531348
2017 dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure. Diabetes 21 28073829
2015 Cross-species inhibition of dUTPase via the Staphylococcal Stl protein perturbs dNTP pool and colony formation in Mycobacterium. DNA repair 21 25841100
2012 Protective effect of human endogenous retrovirus K dUTPase variants on psoriasis susceptibility. The Journal of investigative dermatology 21 22437317
2003 Identification of sequence determinants of human nuclear dUTPase isoform localization. Experimental cell research 21 12799180
2019 CRISPR/Cas9-Mediated Knock-Out of dUTPase in Mice Leads to Early Embryonic Lethality. Biomolecules 20 30987342
2007 Structures of vaccinia virus dUTPase and its nucleotide complexes. Acta crystallographica. Section D, Biological crystallography 20 17452782

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