dc.contributor.author | Scaletti, Emma Rose | |
dc.contributor.author | Vallin, Karl S.A. | |
dc.contributor.author | Bräutigam, Lars | |
dc.contributor.author | Sarno, Antonio | |
dc.contributor.author | Berglund, Ulrika Warpman | |
dc.contributor.author | Helleday, Thomas | |
dc.contributor.author | Stenmark, Pål | |
dc.contributor.author | Jemth, Ann-Sofie | |
dc.date.accessioned | 2021-04-27T07:48:24Z | |
dc.date.available | 2021-04-27T07:48:24Z | |
dc.date.created | 2020-05-07T13:45:37Z | |
dc.date.issued | 2020 | |
dc.identifier.citation | Journal of Biological Chemistry. 2020, 295 (15), 4761-4772. | en_US |
dc.identifier.issn | 0021-9258 | |
dc.identifier.uri | https://hdl.handle.net/11250/2739779 | |
dc.description.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. | en_US |
dc.language.iso | eng | en_US |
dc.publisher | American Society for Biochemistry and Molecular Biology | en_US |
dc.rights | Navngivelse 4.0 Internasjonal | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/deed.no | * |
dc.title | MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool | en_US |
dc.type | Peer reviewed | en_US |
dc.type | Journal article | en_US |
dc.description.version | publishedVersion | en_US |
dc.source.pagenumber | 4761-4772 | en_US |
dc.source.volume | 295 | en_US |
dc.source.journal | Journal of Biological Chemistry | en_US |
dc.source.issue | 15 | en_US |
dc.identifier.doi | 10.1074/jbc.RA120.012636 | |
dc.identifier.cristin | 1809800 | |
dc.relation.project | Samarbeidsorganet mellom Helse Midt-Norge og NTNU: 46056921 | en_US |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |