Affinage

NUDT1

Oxidized purine nucleoside triphosphate hydrolase · UniProt P36639

Length
156 aa
Mass
18.0 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NUDT1 (MTH1) is a Nudix-motif hydrolase that sanitizes the cellular nucleotide pool by hydrolyzing oxidized and modified purine nucleoside triphosphates to their monophosphates, preventing their mis-incorporation into DNA and the resulting mutagenesis (PMID:7713500, PMID:11139615). It was first identified as an 8-oxo-dGTPase that suppresses A:T→C:G transversions (PMID:7713500), and its substrate range was later shown to extend to 2-hydroxy-dATP, 8-oxo-dATP, the ribonucleotide 2-hydroxy-ATP, and O6-methyl-dGTP (PMID:11139615, PMID:30304478). Catalysis depends on conserved Nudix-motif residues (Lys-38, Glu-43, Arg-51, Glu-52) and an amphipathic helix that form the catalytic surface (PMID:9092626, PMID:11376687), while broad substrate accommodation is explained structurally by alternative recognition residues (Asn-33, Trp-117, Asp-119) and an exchange of protonation states at the neighboring active-site aspartates Asp-119/Asp-120 (PMID:11756418, PMID:15133035, PMID:28035004). The enzyme is essential for protecting both nuclear and mitochondrial DNA from oxidative damage: MTH1 loss sensitizes cells to H2O2 and causes 8-oxoguanine accumulation (PMID:12857738), and in mice MTH1 deficiency increases spontaneous tumorigenesis and worsens oxidative nigrostriatal neurodegeneration (PMID:11572992, PMID:16273081). Because cancer cells carry elevated ROS and a more oxidized dNTP pool, they become dependent on MTH1; active-site inhibitors (TH287/TH588, (S)-crizotinib) drive oxidized-dNTP incorporation, DNA damage, and tumor regression in xenografts (PMID:24695224, PMID:24695225). Beyond cancer, MTH1 supports telomere maintenance together with PRDX1 (PMID:29773556), protects platelet mitochondrial bioenergetics during thrombin-induced activation (PMID:37563135), sustains tissue-resident memory CD8+ T cells via a PARP1-TGFβR axis (PMID:35753523), and is co-opted by pulmonary artery smooth muscle cells in pulmonary arterial hypertension (PMID:33021405). MTH1 stability is controlled post-translationally by Skp2-mediated K63-linked polyubiquitination downstream of MAPK signaling (PMID:28947420), and multiple mRNA isoforms generated by alternative splicing and translation initiation direct the protein to cytoplasmic, mitochondrial, and nuclear compartments (PMID:9211940, PMID:11554314).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 High

    Established the founding function of human MTH1 by showing it is an 8-oxo-dGTPase that prevents mutagenic incorporation of oxidized guanine nucleotides, defining nucleotide pool sanitization as its biological role.

    Evidence cDNA expression complementing E. coli mutT- mutator phenotype with direct enzymatic readout

    PMID:7713500

    Open questions at the time
    • Did not define the catalytic residues or structural basis
    • Mammalian in vivo relevance not yet tested
  2. 1997 High

    Mapped the catalytic machinery to specific Nudix-motif residues, showing which side chains are indispensable for 8-oxo-dGTPase activity.

    Evidence Site-directed mutagenesis of MTH1 with bacterial complementation and enzyme assays

    PMID:11376687 PMID:9092626

    Open questions at the time
    • Did not yet explain how oxidized substrates are discriminated from normal nucleotides
    • No three-dimensional structure available
  3. 1997 Medium

    Defined how MTH1 expression and protein diversity are generated, revealing transcriptional control and a polymorphism-influenced isoform repertoire.

    Evidence Promoter-reporter deletion analysis, RT-PCR/5'RACE isoform mapping, and biochemical characterization of the Val83Met variant

    PMID:9013634 PMID:9211940 PMID:9330614

    Open questions at the time
    • Functional consequences of most isoforms not resolved
    • Did not link variants to disease risk
  4. 2001 High

    Expanded MTH1 substrate scope beyond 8-oxo-dGTP and identified residues responsible for substrate discrimination, recasting it as a broad-spectrum sanitizer of oxidized purine nucleotides.

    Evidence HPLC kinetic assays with purified enzyme plus NMR chemical-shift perturbation and mutagenesis

    PMID:11139615 PMID:11756418

    Open questions at the time
    • Catalytic mechanism of phosphate hydrolysis not yet defined
    • Conformational basis of recognition unresolved
  5. 2001 Medium

    Demonstrated that MTH1 isoforms are differentially targeted to mitochondria versus cytoplasm via a SNP-created targeting signal, linking genetic variation to subcellular distribution.

    Evidence SNP/splicing analysis with subcellular fractionation and immunofluorescence

    PMID:11554314

    Open questions at the time
    • Nuclear targeting determinants not defined
    • Quantitative compartment partitioning incomplete
  6. 2003 High

    Provided in vivo proof that MTH1 protects cells and animals from oxidative DNA damage and suppresses tumorigenesis, including epistasis with the base-excision repair gene OGG1.

    Evidence MTH1-null MEFs with mutant rescue, MTH1-knockout and Mth1/Ogg1 double-knockout mouse tumor models

    PMID:11572992 PMID:12615700 PMID:12857738

    Open questions at the time
    • Tissue-specific dependence not dissected
    • Relative contributions of nuclear vs mitochondrial protection unclear
  7. 2004 High

    Defined the catalytic mechanism and conformational substrate recognition through the first solution structure, anchoring substrate specificity to discrete residues.

    Evidence Multidimensional NMR structure with chemical-shift mapping, mutagenesis, and analog hydrolysis assays

    PMID:15095864 PMID:15133035

    Open questions at the time
    • Conflicting conformational assignments (syn vs anti) across studies
    • Tautomer-based specificity not yet established
  8. 2006 High

    Extended the protective role of MTH1 to neurons, showing it guards mitochondrial DNA in dopaminergic neurons against oxidative insult.

    Evidence MPTP challenge in MTH1-null mice with neuropathology and mitochondrial 8-oxoG measurement

    PMID:16273081

    Open questions at the time
    • Did not establish relevance to human neurodegenerative disease
    • Single neurotoxin model
  9. 2011 High

    Refined the structural basis of substrate recognition, proposing tautomer stabilization rather than direct 8-oxo-group contact as the specificity determinant.

    Evidence X-ray structures of free enzyme and 8-oxo-dGMP product complex

    PMID:21787772

    Open questions at the time
    • Mechanism for accommodating chemically distinct substrates not fully reconciled
    • Catalytic protonation states unresolved
  10. 2014 High

    Validated MTH1 as a cancer therapeutic target by showing redox-stressed cancer cells depend on it, and that active-site inhibitors kill tumor cells by promoting oxidized-dNTP incorporation.

    Evidence Co-crystal structures with TH287/TH588 and (S)-crizotinib, cellular incorporation/DNA-damage assays, and patient-derived xenografts

    PMID:24695224 PMID:24695225 PMID:26238318

    Open questions at the time
    • Generality of cancer-cell dependence later debated in the broader field
    • Off-target contributions of some inhibitors not fully excluded
  11. 2017 Medium

    Identified post-translational stabilization as a regulatory layer, showing Skp2-mediated K63 ubiquitination increases MTH1 abundance downstream of MAPK signaling.

    Evidence Reciprocal Co-IP, ubiquitination assays, and Skp2 gain/loss with apoptosis readouts in melanoma cells

    PMID:28947420

    Open questions at the time
    • Ubiquitination sites on MTH1 not mapped
    • Single cancer-cell context
  12. 2018 High

    Established the structural-chemical logic of broad substrate specificity and added O6-methyl-dGTP as a physiologically relevant substrate, linking MTH1 to protection against alkylating agents.

    Evidence Substrate-complex crystal structures with Asp-120 mutagenesis/kinetics; O6-methyl-dGMP co-structure with zebrafish and temozolomide cell models

    PMID:28035004 PMID:30304478

    Open questions at the time
    • Contribution of O6-methyl-dGTP hydrolysis to alkylation chemotherapy response in patients unknown
  13. 2018 High

    Connected MTH1 to genome-stability functions beyond mutation avoidance, showing it cooperates with PRDX1 to sustain telomere length via telomerase.

    Evidence CRISPR double knockout of PRDX1/MTH1 with telomere length and telomerase extension assays

    PMID:29773556

    Open questions at the time
    • Direct molecular link between oxidized-guanine sanitization and telomerase activity not fully defined
  14. 2023 Medium

    Broadened MTH1 biology to non-malignant cell physiology, demonstrating roles in platelet activation/mitochondrial bioenergetics, tissue-resident memory T-cell longevity, and pulmonary vascular remodeling.

    Evidence Conditional/constitutive Nudt1 knockout mice, pharmacological inhibition, platelet and T-cell functional assays, and disease rat models

    PMID:33021405 PMID:35753523 PMID:37563135

    Open questions at the time
    • Whether these phenotypes derive solely from dNTP sanitization vs other activities is unresolved
    • Mechanistic links to PARP1-TGFβR and mitochondrial gene expression are correlative in part

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MTH1 isoform-specific subcellular targeting, post-translational stabilization, and substrate breadth are integrated to determine context-dependent dependence across cancer, vascular, hematological, and immune cells remains unresolved.
  • No unified model linking isoform localization to physiological function
  • Determinants of cell-type-specific MTH1 dependence undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5
Localization
GO:0005739 mitochondrion 4 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
PARP1PRDX1SKP2

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 Human MTH1 (NUDT1) encodes an 8-oxo-dGTPase that hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, preventing A:T to C:G transversion mutations. Expression of the cDNA in E. coli mutT- cells restored normal mutation frequency. cDNA expression in E. coli mutT- complementation assay; genomic cloning Genomics High 7713500
1997 Residues Lys-38, Glu-43, Arg-51, and Glu-52 within the conserved Nudix motif are essential for 8-oxo-dGTPase activity of human MTH1; substitution of any of these abolishes activity. Site-directed mutagenesis of MTH1 cDNA; expression in E. coli mutT- cells; enzyme activity assay Nucleic acids research High 9092626
1997 The Val83Met polymorphism in MTH1 produces a variant protein with more thermolabile 8-oxo-dGTPase activity and altered hydrophobic character, as shown by biochemical and spectroscopic characterization. Protein purification; enzymatic assay; circular dichroism; fluorescence spectroscopy; hydrophobic interaction chromatography Mutation research High 9330614
1997 The mouse MTH1 gene promoter region (−321 to +9) contains the basic promoter activity; a GC-rich region lacks a TATA box and contains AP-1/AP-2 recognition sequences. Expression is regulated at the transcriptional level. Promoter-reporter (CAT) deletion analysis in NIH 3T3 cells; primer extension; S1 mapping The Journal of biological chemistry Medium 9013634
1997 Human MTH1 gene produces at least 7 types of mRNAs via alternative transcription initiation and splicing; a SNP at the 5' splice site (GT to GC) in exon 2 alters splicing patterns. Multiple in-frame ATG codons allow alternative translation initiation. RT-PCR; 5' RACE; nucleotide sequencing of mRNA isoforms The Journal of biological chemistry Medium 9211940
1997 Carcinogenic metals Cu(II), Cd(II), Co(II), and Ni(II) inhibit human MTH1 8-oxo-dGTPase activity in vitro in the presence of Mg(II), with IC50 values of 17 µM (Cu), 30 µM (Cd), 376 µM (Co), 801 µM (Ni). In vitro enzymatic inhibition assay with purified MTH1 protein Carcinogenesis Medium 9328176
2001 Human MTH1 hydrolyzes oxidized purine nucleoside triphosphates including 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxy-dATP, and also the ribonucleotide 2-hydroxy-ATP, with catalytic efficiencies in the order: 2-OH-dATP > 2-OH-ATP > 8-oxo-dGTP > 8-oxo-dATP. HPLC-based kinetic assay with purified recombinant MTH1 Nucleic acids research High 11139615
2001 A SNP in exon 2 of the human MTH1 gene alters splicing and creates an additional mitochondrial targeting signal in a novel p26 polypeptide isoform, directing it to mitochondria in addition to the cytoplasm; the major p18 form is mostly cytoplasmic with some mitochondrial localization. SNP analysis; alternative splicing characterization; subcellular fractionation; immunofluorescence microscopy Progress in nucleic acid research and molecular biology Medium 11554314
2001 Trp-117 is essential for MTH1 to recognize both 8-oxo-dGTP and 2-hydroxy-dATP, while Asp-119 is specifically required for recognition of 2-hydroxy-dATP but not 8-oxo-dGTP, as demonstrated by NMR chemical shift perturbations and mutagenesis. NMR chemical shift perturbation with 8-oxo-dGDP; site-directed mutagenesis; enzymatic activity assay The Journal of biological chemistry High 11756418
2001 The 23-residue conserved phosphohydrolase module (Gly36–Gly58) of MTH1, including an amphipathic alpha-helix (Thr44–Gly58), is functionally equivalent to the corresponding MutT module. Saturated mutagenesis showed the amphipathic property of helix I is essential for maintaining the catalytic surface for 8-oxo-dGTPase activity. Chimeric protein construction; saturated mutagenesis; 8-oxo-dGTPase activity assay Mutation research High 11376687
2001 MTH1-null mouse embryo fibroblasts are highly susceptible to H2O2-induced cell death with accumulation of 8-oxoguanine in both nuclear and mitochondrial DNA. Wild-type hMTH1 rescues this phenotype, while catalytic mutants (defective in 8-oxo-dGTPase or 2-OH-dATPase) only partially rescue, demonstrating that both enzymatic activities contribute to cell protection. MTH1-null MEF generation; H2O2 treatment; HPLC-MS/MS for 8-oxoG measurement; immunofluorescence; rescue by WT and mutant hMTH1 expression The Journal of biological chemistry High 12857738
2001 Spontaneous tumors develop in lungs, livers, and stomachs of MTH1-knockout mice at significantly higher frequency than wild-type, demonstrating that MTH1's dNTP sanitization function suppresses spontaneous tumorigenesis in vivo. Gene targeting to generate MTH1-/- mice; pathological examination at 18 months Proceedings of the National Academy of Sciences of the United States of America High 11572992
2003 Mth1 disruption suppresses lung tumorigenesis in Ogg1-knockout mice despite maintained 8-oxoG accumulation, revealing that Mth1-mediated nucleotide pool sanitization is required for tumor development caused by OGG1 deficiency. Mth1/Ogg1 double-knockout mouse model; tumor incidence scoring; 8-oxoG measurement in DNA Cancer research High 12615700
2004 Solution NMR structure of human MTH1 reveals a fold similar to E. coli MutT despite low sequence similarity outside the Nudix motif. The substrate-binding pocket is at the same position but a pocket-forming helix is displaced ~9 Å. Asn33 is identified as a key residue for discriminating oxidized purines; its mutation modifies substrate specificity. MTH1 catalyzes hydrolysis of 8-oxo-dGTP via nucleophilic substitution of water at the beta-phosphate. Multidimensional heteronuclear NMR spectroscopy; chemical shift perturbation mapping; site-directed mutagenesis; enzymatic assay The Journal of biological chemistry High 15133035
2004 MTH1 recognizes substrates in the syn conformation and requires the 2-amino group of 8-oxo-dGTP and the 6-amino group of 2-hydroxy-dATP for efficient hydrolysis, as demonstrated by testing nucleotide analogs. In vitro hydrolysis assay of nucleotide analogs with purified MTH1 Journal of molecular biology Medium 15095864
2006 MTH1 protects dopamine neurons from oxidative damage in mitochondrial DNA caused by MPTP administration; MTH1-null mice show greater mitochondrial DNA 8-oxoG accumulation and more severe nigrostriatal degeneration after MPTP treatment. MTH1-null mice; MPTP administration; immunohistochemistry for TH and DAT; 8-oxoG measurement in mitochondrial DNA Cell death and differentiation High 16273081
2011 Crystal structures of human MTH1 (1.9 Å) and its complex with product 8-oxo-dGMP (1.8 Å) reveal that the nucleotide binds in the anti conformation with no direct contact between the 8-oxo group and the protein; specificity is proposed to depend on stabilization of the enol tautomer of 8-oxo-dGTP. X-ray crystallography FEBS letters High 21787772
2014 MTH1 is required for cancer cell survival because cancer cells with dysfunctional redox regulation rely on MTH1 to prevent incorporation of oxidized dNTPs (causing DNA damage and cell death). MTH1 inhibitors TH287 and TH588 bind in the active site (co-crystal structures), cause 8-oxo-dNTP incorporation into cancer cell DNA, and produce therapeutic responses in patient-derived xenografts. Co-crystal structures; cell viability assays; 8-oxo-dG incorporation measurement; patient-derived mouse xenograft models; siRNA knockdown Nature High 24695224
2014 (S)-crizotinib selectively inhibits MTH1 catalytic activity at nanomolar concentrations (the (R)-enantiomer is inactive), binds in the MTH1 active site (co-crystal structure), increases DNA single-strand breaks and activates DNA repair in cancer cells, and suppresses tumor growth in animal models. Enzymatic assay; chemical proteomics; co-crystal structure; kinome-wide profiling; cellular DNA damage assays; xenograft models Nature High 24695225
2015 Crystal structure of MTH1 with inhibitors TH287/TH588 in the active site; structural basis for selective inhibition defined. Key structural features distinguish MTH1 from NUDT15 (MTH2), explaining different substrate preferences. X-ray crystallography of MTH1-inhibitor complexes; substrate hydrolysis assays; cellular 8-oxo-dGTP incorporation assay; siRNA knockdown Nature communications High 26238318
2016 MTH1 recognizes diverse oxidized nucleotides via an exchange of protonation states at two neighboring aspartate residues (Asp-119 and Asp-120) in its substrate-binding pocket, accounting for its broad substrate specificity. Crystal structures of hMTH1 in complex with 8-oxo-dGTP and 2-oxo-dATP at neutral pH reveal that both substrates use the same catalytic Nudix motif alignment but different hydrogen-bonding patterns. X-ray crystallography of substrate complexes; kinetic assays on Asp-120 mutants (D120N, D120A); high-resolution bond-length analysis The Journal of biological chemistry High 28035004
2017 MTH1 is regulated post-translationally by Skp2-mediated K63-linked polyubiquitination via the SCF ubiquitin ligase complex, which stabilizes MTH1 rather than targeting it for degradation, protecting melanoma cells from oxidative stress-induced DNA damage. MAPK signaling upregulates Skp2 to increase MTH1 stability. Co-immunoprecipitation; ubiquitination assay; Skp2 overexpression/knockdown; MTH1 expression measurement; apoptosis assay Cancer research Medium 28947420
2018 MTH1 efficiently catalyzes hydrolysis of O6-methyl-dGTP with catalytic efficiency similar to 8-oxo-dGTP; this activity is unique to MTH1 among human NUDIX proteins and is conserved in evolution. Co-crystal structure of MTH1 with O6-methyl-dGMP is presented. MTH1 deficiency sensitizes human cells to the alkylating agent temozolomide, and zebrafish survival after O6-methyl-dGTP microinjection depends on active MTH1. In vitro hydrolysis assay; crystal structure of MTH1-O6-methyl-dGMP; zebrafish microinjection model; cell viability assay with temozolomide Nucleic acids research High 30304478
2018 PRDX1 and MTH1 cooperate to prevent accumulation of oxidized guanine in the genome. Concomitant disruption of PRDX1 and MTH1 genes in cancer cells causes ROS-concentration-dependent continuous telomere shortening due to efficient inhibition of telomere extension by telomerase, identifying these antioxidant systems as required for telomere maintenance. CRISPR/Cas9 knockout of PRDX1 and MTH1; telomere length measurement; telomerase extension assay; ROS measurement Genes & development High 29773556
2022 NUDT1 promotes accumulation and longevity of CD103+ tissue-resident memory CD8+ T cells (TRM) via PARP1-TGFβR axis-dependent DNA damage resistance. NUDT1 blockade suppresses cytotoxic effector functions upon PDC-E2 re-stimulation; PARP1 inhibition restores NUDT1-deficient TRM cell survival and TGFβ-Smad signaling. Conditional Nudt1 knockout mice; adoptive co-transfer; NUDT1 overexpression/inhibition in vitro; PARP1 inhibitor rescue experiment; flow cytometry; 3D organoid co-culture cytotoxicity assay Journal of hepatology Medium 35753523
2023 MTH1 is expressed in platelets and its deficiency impairs thrombin-induced (but not CRP-induced) platelet aggregation, phosphatidylserine exposure, calcium mobilization, and mitochondrial ATP production. Mechanistically, MTH1 deficiency causes mitochondrial DNA oxidative damage and reduces cytochrome c oxidase 1 expression, linking MTH1 to mitochondrial bioenergetics in platelets. MTH1-deficient mice; platelet function assays; mitochondrial ROS measurement; mitochondrial DNA oxidative damage assay; cytochrome c oxidase 1 western blot; in vivo thrombosis models Nature communications High 37563135
2010 MTH1, MTH2, and NUDT5 all suppress A:T→C:G substitution mutations induced by 8-OH-dGTP in human cells; triple knockdown of all three increases mutation frequency more than any single knockdown, indicating additive roles in dNTP pool sanitization. siRNA knockdown; shuttle plasmid supF mutation assay in human 293T cells Free radical biology & medicine Medium 20144704
2021 NUDT1 overexpression in PAH pulmonary artery smooth muscle cells prevents incorporation of oxidized nucleotides into DNA, enabling escape from apoptosis and proliferation. Molecular or pharmacological inhibition of NUDT1 in PAH-PASMCs induces irresolvable DNA damage (comet assay), disrupted bioenergetics (Seahorse assay), and cell death. Pharmacological inhibition of NUDT1 in two PAH rat models decreased pulmonary vascular remodeling. Proteomics; comet assay; Seahorse bioenergetics assay; TUNEL assay; siRNA knockdown; pharmacological inhibition; monocrotaline and Sugen/hypoxia rat models American journal of respiratory and critical care medicine High 33021405

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature 419 24695224
2014 Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature 321 24695225
2001 Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase. Proceedings of the National Academy of Sciences of the United States of America 256 11572992
2003 Ogg1 knockout-associated lung tumorigenesis and its suppression by Mth1 gene disruption. Cancer research 209 12615700
2011 MiR-145 inhibits cell proliferation of human lung adenocarcinoma by targeting EGFR and NUDT1. RNA biology 179 21289483
2001 Regulation of intracellular localization of human MTH1, OGG1, and MYH proteins for repair of oxidative DNA damage. Progress in nucleic acid research and molecular biology 133 11554314
1994 Genomic structure and chromosome location of the human mutT homologue gene MTH1 encoding 8-oxo-dGTPase for prevention of A:T to C:G transversion. Genomics 132 7713500
2003 Grr1-dependent inactivation of Mth1 mediates glucose-induced dissociation of Rgt1 from HXT gene promoters. Molecular biology of the cell 128 12925759
2003 An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress. The Journal of biological chemistry 116 12857738
2016 Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival. Journal of medicinal chemistry 111 26878898
2001 Human MTH1 protein hydrolyzes the oxidized ribonucleotide, 2-hydroxy-ATP. Nucleic acids research 109 11139615
2001 Molecular genetics and structural biology of human MutT homolog, MTH1. Mutation research 106 11376687
2016 Validation and development of MTH1 inhibitors for treatment of cancer. Annals of oncology : official journal of the European Society for Medical Oncology 104 27827301
2012 Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2. The Journal of biological chemistry 98 22556419
2015 Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. Nature communications 93 26238318
2000 Mth1 receives the signal given by the glucose sensors Snf3 and Rgt2 in Saccharomyces cerevisiae. Molecular microbiology 93 10632886
1995 Mouse MTH1 protein with 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphatase activity that prevents transversion mutation. cDNA cloning and tissue distribution. The Journal of biological chemistry 91 7592783
2016 Proteomic profiling of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival. Scientific reports 84 27210421
2002 Mutational specificity of mice defective in the MTH1 and/or the MSH2 genes. DNA repair 78 12531017
2014 MutT Homolog 1 (MTH1) maintains multiple KRAS-driven pro-malignant pathways. Oncogene 77 25023700
2003 Repression of transcription by Rgt1 in the absence of glucose requires Std1 and Mth1. Current genetics 74 14508605
2011 Crystal structure of human MTH1 and the 8-oxo-dGMP product complex. FEBS letters 72 21787772
2006 MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Cell death and differentiation 72 16273081
2001 A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1. The Journal of biological chemistry 72 11756418
2020 MTH1 inhibitor amplifies the lethality of reactive oxygen species to tumor in photodynamic therapy. Science advances 70 32181355
2012 An internal deletion in MTH1 enables growth on glucose of pyruvate-decarboxylase negative, non-fermentative Saccharomyces cerevisiae. Microbial cell factories 68 22978798
2006 MTH1, an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides. DNA repair 65 16621731
2018 PRDX1 and MTH1 cooperate to prevent ROS-mediated inhibition of telomerase. Genes & development 64 29773556
1997 Regulation of expression of the human MTH1 gene encoding 8-oxo-dGTPase. Alternative splicing of transcription products. The Journal of biological chemistry 60 9211940
2016 Identification of potent and selective MTH1 inhibitors. Bioorganic & medicinal chemistry letters 57 26898335
2006 MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced excitotoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience 55 16467516
2016 MTH1 as a nucleotide pool sanitizing enzyme: Friend or foe? Free radical biology & medicine 54 27833032
2010 Programmed cell death triggered by nucleotide pool damage and its prevention by MutT homolog-1 (MTH1) with oxidized purine nucleoside triphosphatase. Mutation research 54 20542142
2017 MTH1 as a Chemotherapeutic Target: The Elephant in the Room. Cancers 53 28481306
2010 Suppression of mutagenesis by 8-hydroxy-2'-deoxyguanosine 5'-triphosphate (7,8-dihydro-8-oxo-2'-deoxyguanosine 5'-triphosphate) by human MTH1, MTH2, and NUDT5. Free radical biology & medicine 53 20144704
2004 Structure of human MTH1, a Nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates. The Journal of biological chemistry 52 15133035
2019 Augment of Oxidative Damage with Enhanced Photodynamic Process and MTH1 Inhibition for Tumor Therapy. Nano letters 51 31262183
2022 NUDT1 promotes the accumulation and longevity of CD103+ TRM cells in primary biliary cholangitis. Journal of hepatology 49 35753523
2008 Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3. Gut 49 18515411
2003 Increase of human MTH1 and decrease of 8-hydroxydeoxyguanosine in leukocyte DNA by acute and chronic exercise in healthy male subjects. Biochemical and biophysical research communications 49 12745079
2018 Delivery of MTH1 inhibitor (TH287) and MDR1 siRNA via hyaluronic acid-based mesoporous silica nanoparticles for oral cancers treatment. Colloids and surfaces. B, Biointerfaces 47 30352381
2017 Skp2-Mediated Stabilization of MTH1 Promotes Survival of Melanoma Cells upon Oxidative Stress. Cancer research 47 28947420
2023 MTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis. Nature communications 45 37563135
1997 Biochemical and physicochemical characterization of normal and variant forms of human MTH1 protein with antimutagenic activity. Mutation research 45 9330614
2000 The HTR1 gene is a dominant negative mutant allele of MTH1 and blocks Snf3- and Rgt2-dependent glucose signaling in yeast. Journal of bacteriology 44 10629208
2021 MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis. Scientific reports 43 33758207
2020 lncRNA AFAP1-AS1 promotes triple negative breast cancer cell proliferation and invasion via targeting miR-145 to regulate MTH1 expression. Scientific reports 43 32376943
2017 Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target. ACS chemical biology 42 28679043
2007 Genetic investigation of DNA-repair pathway genes PMS2, MLH1, MSH2, MSH6, MUTYH, OGG1 and MTH1 in sporadic colon cancer. International journal of cancer 39 17417778
2015 Echinacoside induces apoptotic cancer cell death by inhibiting the nucleotide pool sanitizing enzyme MTH1. OncoTargets and therapy 38 26677335
2015 MTH1 expression is required for effective transformation by oncogenic HRAS. Oncotarget 37 25893378
2017 The role of miR-485-5p/NUDT1 axis in gastric cancer. Cancer cell international 36 29075149
2017 Glioblastoma and glioblastoma stem cells are dependent on functional MTH1. Oncotarget 36 29156675
2012 Human Mut T Homolog 1 (MTH1): a roadblock for the tumor-suppressive effects of oncogenic RAS-induced ROS. Small GTPases 35 22790201
2020 TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model. EBioMedicine 34 32151797
2020 Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives. Acta pharmaceutica Sinica. B 33 33354500
2016 Birth of MTH1 as a therapeutic target for glioblastoma: MTH1 is indispensable for gliomatumorigenesis. American journal of translational research 33 27398163
2011 Analysis of the oxidative damage repair genes NUDT1, OGG1, and MUTYH in patients from mismatch repair proficient HNPCC families (MSS-HNPCC). Clinical cancer research : an official journal of the American Association for Cancer Research 33 21355073
2011 Oxidative damage to RNA and expression patterns of MTH1 in the hippocampi of senescence-accelerated SAMP8 mice and Alzheimer's disease patients. Neurochemical research 33 21538080
2001 Analysis of MTH1 gene function in mice with targeted mutagenesis. Mutation research 33 11376688
2022 A multifunctional non-viral vector for the delivery of MTH1-targeted CRISPR/Cas9 system for non-small cell lung cancer therapy. Acta biomaterialia 32 36162766
2021 Oxidized DNA Precursors Cleanup by NUDT1 Contributes to Vascular Remodeling in Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine 31 33021405
2015 Addiction to MTH1 protein results in intense expression in human breast cancer tissue as measured by liquid chromatography-isotope-dilution tandem mass spectrometry. DNA repair 31 26202347
2013 Mth1 regulates the interaction between the Rgt1 repressor and the Ssn6-Tup1 corepressor complex by modulating PKA-dependent phosphorylation of Rgt1. Molecular biology of the cell 31 23468525
2004 Expression of DNA repair protein: MYH, NTH1, and MTH1 in colorectal cancer. Hepato-gastroenterology 31 15143881
2019 Potent and specific MTH1 inhibitors targeting gastric cancer. Cell death & disease 30 31164636
2004 Probing the substrate recognition mechanism of the human MTH1 protein by nucleotide analogs. Journal of molecular biology 30 15095864
2017 (S)-crizotinib induces apoptosis in human non-small cell lung cancer cells by activating ROS independent of MTH1. Journal of experimental & clinical cancer research : CR 29 28882182
2019 The MTH1 inhibitor TH588 is a microtubule-modulating agent that eliminates cancer cells by activating the mitotic surveillance pathway. Scientific reports 28 31604991
2018 Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design. Journal of medicinal chemistry 28 29485874
2019 Increased MTH1-specific 8-oxodGTPase activity is a hallmark of cancer in colon, lung and pancreatic tissue. DNA repair 27 31311767
2018 Overexpression of MTH1 and OGG1 proteins in ulcerative colitis-associated carcinogenesis. Oncology letters 27 30008864
2018 MutT homologue 1 (MTH1) catalyzes the hydrolysis of mutagenic O6-methyl-dGTP. Nucleic acids research 27 30304478
1997 Sensitivity of Escherichia coli (MutT) and human (MTH1) 8-oxo-dGTPases to in vitro inhibition by the carcinogenic metals, nickel(II), copper(II), cobalt(II) and cadmium(II). Carcinogenesis 27 9328176
2007 Analysis of the base excision repair genes MTH1, OGG1 and MUTYH in patients with squamous oral carcinomas. Oral oncology 26 17207658
2019 Mechanisms of MTH1 inhibition-induced DNA strand breaks: The slippery slope from the oxidized nucleotide pool to genotoxic damage. DNA repair 25 30852368
2016 Structural and Kinetic Studies of the Human Nudix Hydrolase MTH1 Reveal the Mechanism for Its Broad Substrate Specificity. The Journal of biological chemistry 25 28035004
2021 MTH1 Inhibitor TH1579 Induces Oxidative DNA Damage and Mitotic Arrest in Acute Myeloid Leukemia. Cancer research 24 34593524
2019 Differential anti-tumour effects of MTH1 inhibitors in patient-derived 3D colorectal cancer cultures. Scientific reports 24 30692572
2006 Association of polymorphisms in the MTH1 gene with small cell lung carcinoma risk. Carcinogenesis 24 16774934
1997 Significance of the conserved amino acid sequence for human MTH1 protein with antimutator activity. Nucleic acids research 24 9092626
2019 Dual Inhibitors of 8-Oxoguanine Surveillance by OGG1 and NUDT1. ACS chemical biology 23 31622553
2017 Synergistic therapy of chemotherapeutic drugs and MTH1 inhibitors using a pH-sensitive polymeric delivery system for oral squamous cell carcinoma. Biomaterials science 23 28744533
2015 Influence of Chirality of Crizotinib on Its MTH1 Protein Inhibitory Activity: Insight from Molecular Dynamics Simulations and Binding Free Energy Calculations. PloS one 22 26677850
2007 MYH, OGG1, MTH1, and APC alterations involved in the colorectal tumorigenesis of Korean patients with multiple adenomas. Virchows Archiv : an international journal of pathology 22 17252231
2020 MTH1 Inhibitor TH588 Disturbs Mitotic Progression and Induces Mitosis-Dependent Accumulation of Genomic 8-oxodG. Cancer research 21 32312836
2015 AuNP flares-capped mesoporous silica nanoplatform for MTH1 detection and inhibition. Biomaterials 21 26298289
2021 A Double-Edged Sword: The Anti-Cancer Effects of Emodin by Inhibiting the Redox-Protective Protein MTH1 and Augmenting ROS in NSCLC. Journal of Cancer 20 33403025
2016 MTH1 Substrate Recognition--An Example of Specific Promiscuity. PloS one 20 26999531
2020 AXL and CAV-1 play a role for MTH1 inhibitor TH1579 sensitivity in cutaneous malignant melanoma. Cell death and differentiation 19 31919461
2018 The roles of human MTH1, MTH2 and MTH3 proteins in maintaining genome stability under oxidative stress. Mutation research 19 29482072
2017 Farnesyl phenolic enantiomers as natural MTH1 inhibitors from Ganoderma sinense. Oncotarget 19 29221173
2017 TH588, an MTH1 inhibitor, enhances phenethyl isothiocyanate-induced growth inhibition in pancreatic cancer cells. Oncology letters 19 29435064
2024 Role of MTH1 in oxidative stress and therapeutic targeting of cancer. Redox biology 18 39418911
2018 Hepatitis B Virus X Protein Increases 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine (8-Oxodg) Level via Repressing MTH1/ MTH2 Expression in Hepatocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 18 30448843
2016 A Chimeric ATP-Linked Nucleotide Enables Luminescence Signaling of Damage Surveillance by MTH1, a Cancer Target. Journal of the American Chemical Society 18 27413803
1997 Organization and expression of the mouse MTH1 gene for preventing transversion mutation. The Journal of biological chemistry 18 9013634
2023 Fusobacterium nucleatum facilitates proliferation and autophagy by activating miR-361-3p/NUDT1 axis through oxidative stress in hypopharyngeal squamous cell carcinoma. BMC cancer 17 37848855
2022 Targeting the DNA repair enzymes MTH1 and OGG1 as a novel approach to treat inflammatory diseases. Basic & clinical pharmacology & toxicology 16 35708697
2021 MTH1 Inhibitors for the Treatment of Psoriasis. The Journal of investigative dermatology 16 33676948

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