Alternative titles; symbols
HGNC Approved Gene Symbol: NUDT1
Cytogenetic location: 7p22.3 Genomic coordinates (GRCh38): 7:2,242,226-2,251,145 (from NCBI)
Oxygen radicals, which can be produced through normal cellular metabolism, are thought to play an important role in mutagenesis and tumorigenesis. Among various classes of oxidative DNA damage, 8-oxo-7,8-dihydroguanine (8-oxoG) is most important because of its abundance and mutagenicity. The product of the MTH1 gene hydrolyzes 8-oxo-dGTP to monophosphate in the nucleotide pool, thereby preventing occurrence of transversion mutations (summary by Tsuzuki et al., 2001).
Sakumi et al. (1993) purified NUDT1 from Jurkat human T cells. By sequencing peptide fragments, followed by PCR analysis of Jurkat and HeLa cell cDNA libraries, they cloned full-length NUDT1. The deduced protein contains 156 amino acids and has a calculated molecular mass of approximately 17.9 kD. It has a 24-amino acid motif similar to the central catalytic region of E. coli mutT. Gel-filtration analysis detected NUDT1 at a position corresponding to 18 kD.
By sequencing MTH1 clones obtained from Jurkat cells, Oda et al. (1997) identified 7 MTH1 variants that differ in splicing of exons 1 and 2 and that contain different AUG translational start codons. The major variant, which contains exon 1a and lacks exon 2, was predicted to encode an 18-kD protein. Northern blot analysis detected a 0.8-kb MTH1 transcript variably expressed in most of the 21 tissues and 2 cell lines examined. Highest expression was detected in Jurkat cells, followed by testis, thymus, and HeLa cells. Western blot analysis detected multiple MTH1 proteins in crude extracts from various human cell lines. A fraction of MTH1 existed in the mitochondrial matrix.
By Western blot analysis of in vitro-translated protein, Oda et al. (1999) found that the 7 main MTH1 splice variants encoded proteins with apparent molecular masses of 22, 21, and 18 kD. A polymorphic alteration (GU-to-GC) at the beginning of exon 2c converts an in-frame UGA to CGA, yielding another UGA further upstream and producing an additional polypeptide of 26 kD. The MTH1 isoforms have unique N-terminal sequences, but they all contain the catalytic Nudix motif.
Furuichi et al. (1994) isolated the genomic sequence encoding NUDT1, which they called MTH1. They determined that the NUDT1 gene is composed of at least 4 exons and spans approximately 9 kb.
Igarashi et al. (1997) showed that the mouse Mth1 gene consists of 5 exons spanning about 6 kb of genomic DNA; the first 2 exons are noncoding. The authors confirmed that the human gene contains 4 exons, the first of which is noncoding.
Oda et al. (1997) determined that the NUDT1 gene contains 5 major exons. There are 2 contiguous alternative sequences of exon 1 (1a and 1b) and 3 contiguous alternative segments of exon 2 (2a, 2b, and 2c). Most NUDT1 transcripts have 3 alternative translational start sites, and a SNP introduces an additional translational start site. The 5-prime upstream region lacks TATA or CCAAT sequences, but it is highly GC rich and has potential SP1 (189906)-binding sites. NUDT1 also has potential binding sites for ETS family proteins (see 164720).
By fluorescence in situ hybridization, Furuichi et al. (1994) mapped the NUDT1 gene to chromosome 7p22.
E. coli cells deleted from the mutT gene have an elevated mutation frequently compared to wildtype cells. Sakumi et al. (1993) found that expression of human NUDT1 in mutT-negative E. coli increased 8-oxo-dGTPase activity and reduced mutation frequency compared with control mutT-negative cells.
Using Northern blot analysis, Oda et al. (1997) found that expression of MTH1 was low in quiescent human lymphocytes, but that it increased in lymphocytes that were stimulated to proliferate. Oda et al. (1997) stated that all MTH1 isoforms hydrolyze 8-oxo-GTP.
Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free deoxynucleoside triphosphates (dNTPs). The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is nonessential in normal cells, Gad et al. (2014) showed that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. Gad et al. (2014) validated MTH1 as an anticancer target in vivo and described small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein cocrystal structures demonstrated that the inhibitors bind in the active site of MTH1. The inhibitors caused incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity, and therapeutic responses in patient-derived mouse xenografts. Gad et al. (2014) concluded that this study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic-lethal.
Huber et al. (2014) used a chemical proteomic approach to identify MTH1, a nucleotide pool-sanitizing enzyme, as the target of small molecule SCH51344. Loss of function of MTH1 impaired growth of KRAS (190070) tumor cells, whereas MTH1 overexpression mitigated sensitivity toward SCH51344. Searching for more drug-like inhibitors, Huber et al. (2014) identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 activity. Surprisingly, the clinically used R-enantiomer of the drug was inactive, whereas the S-enantiomer selectively inhibited MTH1 catalytic activity. Enzymatic assays, chemical proteomic profiling, kinomewide activity surveys, and MTH1 cocrystal structures of both enantiomers provided a rationale for this remarkable stereospecificity. Disruption of nucleotide pool homeostasis via MTH1 inhibition by S-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumor growth in animal models. Huber et al. (2014) concluded that their results identified S-crizotinib as an attractive chemical entity for further preclinical evaluation, and small-molecule inhibitors of MTH1 in general as a promising novel class of anticancer agents.
Mishima et al. (2004) presented the solution structure of 156-amino acid recombinant human MTH1. Although the sequence identity between human MTH1 and E. coli mutT is as low as 9.3% outside the Nudix motif, their overall alpha-plus-beta folds appeared similar. The Nudix motif (residues 37-59) of MTH1 adopted an amphipathic helix of approximately 3 turns and a preceding hairpin-like loop, and it formed part of a putative nucleotide-binding pocket. The nucleotide-binding pocket was predicted to bind the base moiety of ligand nucleotides, and acidic residues of the Nudix motif were predicted to bind the phosphate groups of the substrate indirectly via coordinated metals. Upon mixing, MTH1 bound 8-oxo-dGDP in a 1:1 ratio. Binding of 8-oxo-dGDP or 2-OH-dADP resulted in a positional shift in residues in the hydrophobic pocket.
Tsuzuki et al. (2001) found that Mth1-null mice appeared normal. However, at 18 months of age they showed higher tumor incidence than wildtype, particularly in lung, liver, and stomach. No clear abnormalities were seen in 12-month-old Mth1-null mice. Mth1-null cells showed an elevated mutation rate.
Furuichi, M., Yoshida, M. C., Oda, H., Tajiri, T., Nakabeppu, Y., Tsuzuki, T., Sekiguchi, M. 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 24: 485-490, 1994. [PubMed: 7713500] [Full Text: https://doi.org/10.1006/geno.1994.1657]
Gad, H., Koolmeister, T., Jemth, A.-S., Eshtad, S., Jacques, S. A., Strom, C. E., Svensson, L. M., Schultz, N., Lundback, T., Einarsdottir, B. O., Saleh, A., Gokturk, C., and 45 others. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature 508: 215-221, 2014. Note: Erratum: Nature 544: 508 only, 2017. [PubMed: 24695224] [Full Text: https://doi.org/10.1038/nature13181]
Huber, K. V. M., Salah, E., Radic, B., Gridling, M., Elkins, J. M., Stukalov, A., Jemth, A.-S., Gokturk, C., Sanjiv, K., Stromberg, K., Pham, T., Berglund, U. W., Colinge, J., Bennett, K. L., Loizou, J. I., Helleday, T., Knapp, S., Superti-Furga, G. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature 508: 222-227, 2014. [PubMed: 24695225] [Full Text: https://doi.org/10.1038/nature13194]
Igarashi, H., Tsuzuki, T., Kakuma, T., Tominaga, Y., Sekiguchi, M. Organization and expression of the mouse MTH1 gene for preventing transversion mutation. J. Biol. Chem. 272: 3766-3772, 1997. [PubMed: 9013634] [Full Text: https://doi.org/10.1074/jbc.272.6.3766]
Mishima, M., Sakai, Y., Itoh, N., Kamiya, H., Furuichi, M., Takahashi, M., Yamagata, Y., Iwai, S., Nakabeppu, Y., Shirakawa, M. Structure of human MTH1, a Nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates. J. Biol. Chem. 279: 33806-33815, 2004. [PubMed: 15133035] [Full Text: https://doi.org/10.1074/jbc.M402393200]
Oda, H., Nakabeppu, Y., Furuichi, M., Sekiguchi, M. Regulation of expression of the human MTH1 gene encoding 8-oxo-dGTPase: alternative splicing of transcription products. J. Biol. Chem. 272: 17843-17850, 1997. [PubMed: 9211940] [Full Text: https://doi.org/10.1074/jbc.272.28.17843]
Oda, H., Taketomi, A., Maruyama, R., Itoh, R., Nishioka, K., Yakushiji, H., Suzuki, T., Sekiguchi, M., Nakabeppu, Y. Multi-forms of human MTH1 polypeptides produced by alternative translation initiation and single nucleotide polymorphism. Nucleic Acids Res. 27: 4335-4343, 1999. [PubMed: 10536140] [Full Text: https://doi.org/10.1093/nar/27.22.4335]
Sakumi, K., Furuichi, M., Tsuzuki, T., Kakuma, T., Kawabata, S., Maki, H., Sekiguchi, M. Cloning and expression of cDNA for a human enzyme that hydrolyzes 8-oxo-dGTP, a mutagenic substrate for DNA synthesis. J. Biol. Chem. 268: 23524-23530, 1993. [PubMed: 8226881]
Tsuzuki, T., Egashira, A., Igarashi, H., Iwakuma, T., Nakatsuru, Y., Tominaga, Y., Kawate, H., Nakao, K., Nakamura, K., Ide, F., Kura, S., Nakabeppu, Y., Katsuki, M., Ishikawa, T., Sekiguchi, M. Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase. Proc. Nat. Acad. Sci. 98: 11456-11461, 2001. [PubMed: 11572992] [Full Text: https://doi.org/10.1073/pnas.191086798]