{"entity": "publication", "iuid": "e8c5934c61524c688421a2e4b3dd5c20", "timestamp": "2026-08-20T20:50:46.952Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/e8c5934c61524c688421a2e4b3dd5c20.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/e8c5934c61524c688421a2e4b3dd5c20"}}, "title": "MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool.", "authors": [{"family": "Scaletti", "given": "Emma Rose", "initials": "ER"}, {"family": "Vallin", "given": "Karl S", "initials": "KS"}, {"family": "Br\u00e4utigam", "given": "Lars", "initials": "L"}, {"family": "Sarno", "given": "Antonio", "initials": "A", "orcid": "0000-0002-9308-8018", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/22883e442f534ba99f2917cf45d95b3d.json"}}, {"family": "Warpman Berglund", "given": "Ulrika", "initials": "U"}, {"family": "Helleday", "given": "Thomas", "initials": "T"}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9791bc0d7463417899d6953b5ca1bac3.json"}}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "AS", "orcid": "0000-0002-7550-1833", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/51f26d370fb74994b8e2b4fa1c9c2f7a.json"}}], "type": "journal article", "published": "2020-04-10", "journal": {"title": "J Biol Chem", "issn": "1083-351X", "volume": "295", "issue": "15", "pages": "4761-4772", "issn-l": "0021-9258"}, "abstract": "MutT homologue 1 (MTH1) removes oxidized nucleotides from the nucleotide pool and thereby prevents their incorporation into the genome and thereby reduces genotoxicity. We previously reported that MTH1 is an efficient catalyst of O6-methyl-dGTP hydrolysis suggesting that MTH1 may also sanitize the nucleotide pool from other methylated nucleotides. We here show that MTH1 efficiently catalyzes the hydrolysis of N6-methyl-dATP to N6-methyl-dAMP and further report that N6-methylation of dATP drastically increases the MTH1 activity. We also observed MTH1 activity with N6-methyl-ATP, albeit at a lower level. We show that N6-methyl-dATP is incorporated into DNA in vivo, as indicated by increased N6-methyl-dA DNA levels in embryos developed from MTH1 knock-out zebrafish eggs microinjected with N6-methyl-dATP compared with noninjected embryos. N6-methyl-dATP activity is present in MTH1 homologues from distantly related vertebrates, suggesting evolutionary conservation and indicating that this activity is important. Of note, N6-methyl-dATP activity is unique to MTH1 among related NUDIX hydrolases. Moreover, we present the structure of N6-methyl-dAMP-bound human MTH1, revealing that the N6-methyl group is accommodated within a hydrophobic active-site subpocket explaining why N6-methyl-dATP is a good MTH1 substrate. N6-methylation of DNA and RNA has been reported to have epigenetic roles and to affect mRNA metabolism. We propose that MTH1 acts in concert with adenosine deaminase-like protein isoform 1 (ADAL1) to prevent incorporation of N6-methyl-(d)ATP into DNA and RNA. This would hinder potential dysregulation of epigenetic control and RNA metabolism via conversion of N6-methyl-(d)ATP to N6-methyl-(d)AMP, followed by ADAL1-catalyzed deamination producing (d)IMP that can enter the nucleotide salvage pathway.", "doi": "10.1074/jbc.RA120.012636", "pmid": "32144205", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC7152754"}, {"db": "pii", "key": "S0021-9258(17)48573-5"}, {"db": "PDB", "key": "3ZR1"}, {"db": "PDB", "key": "3ZR0"}, {"db": "PDB", "key": "5OTM"}, {"db": "PDB", "key": "6QVO"}, {"db": "PDB", "key": "5OTN"}, {"db": "PDB", "key": "6FL4"}, {"db": "PDB", "key": "3A6T"}], "notes": [], "created": "2026-08-20T09:32:21.804Z", "modified": "2026-08-20T09:32:21.945Z"}