ArticleNucleic acids research2018
MutT homologue 1 (MTH1) catalyzes the hydrolysis of mutagenic O6-methyl-dGTP.
Article in Nucleic acids research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 32 citations in OpenAlex.
- Enzymatic catabolism of the mutagenic DNA precursor, 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP), in rainbow trout liver.Fish physiology and biochemistry · 2026Article
- Article
- Identification of shared diagnostic biomarkers and potential co-morbidity mechanisms between primary Sjogren's syndrome and chronic kidney disease.Clinical rheumatology · 2025Article
- Article
- Repurposing resveratrol for redox-mediated inhibition of MTH1 in breast cancer.Scientific reports · 2025Article
- Neutron and time-resolved X-ray crystallography reveal the substrate recognition and catalytic mechanism of human Nudix hydrolase MTH1.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Role of MTH1 in oxidative stress and therapeutic targeting of cancer.Redox biology · 2024Review
- Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability.Nature communications · 2024Article
- Targeting MutT Homolog 1 (MTH1) for Breast Cancer Suppression by Using a Novel MTH1 Inhibitor MA-24 with Tumor-Selective Toxicity.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Targeting the nucleic acid oxidative damage repair enzyme MTH1: a promising therapeutic option.Frontiers in cell and developmental biology · 2024Review
- Mammalian Nudt15 hydrolytic and binding activity on methylated guanosine mononucleotides.European biophysics journal : EBJ · 2023Article
- Targeting the DNA damage response and repair in cancer through nucleotide metabolism.Molecular oncology · 2022Review
- Biomarkers of nucleic acid oxidation - A summary state-of-the-art.Redox biology · 2021Article
- Current perspectives on the clinical implications of oxidative RNA damage in aging research: challenges and opportunities.GeroScience · 2021Review
- Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma.Scientific reports · 2021Article
- Transcriptional mutagenesis dramatically alters genome-wide p53 transactivation landscape.Scientific reports · 2020Article
- MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool.The Journal of biological chemistry · 2020Article
- Mechanisms of MTH1 inhibition-induced DNA strand breaks: The slippery slope from the oxidized nucleotide pool to genotoxic damage.DNA repair · 2019Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nucleotides in the free pool are more susceptible to nonenzymatic methylation than those protected in the DNA double helix. Methylated nucleotides like O6-methyl-dGTP can be mutagenic and toxic if incorporated into DNA. Removal of methylated nucleotides from the nucleotide pool may therefore be important to maintain genome integrity. We show that MutT homologue 1 (MTH1) efficiently catalyzes the hydrolysis of O6-methyl-dGTP with a catalytic efficiency similar to that for 8-oxo-dGTP. O6-methyl-dGTP activity is exclusive to MTH1 among human NUDIX proteins and conserved through evolution but not found in bacterial MutT. We present a high resolution crystal structure of human and zebrafish MTH1 in complex with O6-methyl-dGMP. By microinjecting fertilized zebrafish eggs with O6-methyl-dGTP and inhibiting MTH1 we demonstrate that survival is dependent on active MTH1 in vivo. O6-methyl-dG levels are higher in DNA extracted from zebrafish embryos microinjected with O6-methyl-dGTP and inhibition of O6-methylguanine-DNA methyl transferase (MGMT) increases the toxicity of O6-methyl-dGTP demonstrating that O6-methyl-dGTP is incorporated into DNA. MTH1 deficiency sensitizes human cells to the alkylating agent Temozolomide, a sensitization that is more pronounced upon MGMT inhibition. These results expand the cellular MTH1 function and suggests MTH1 also is important for removal of methylated nucleotides from the nucleotide pool.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.