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Sökning: onr:"swepub:oai:DiVA.org:su-181859" > MutT homologue 1 (M...

  • Scaletti, Emma RoseStockholm University,Lunds universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Lund University, Sweden,Strukturell biokemi,Forskargrupper vid Lunds universitet,Structural Biochemistry,Lund University Research Groups (författare)

MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool

  • Artikel/kapitelEngelska2020

Förlag, utgivningsår, omfång ...

  • 2020
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:su-181859
  • https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-181859URI
  • https://doi.org/10.1074/jbc.RA120.012636DOI
  • https://lup.lub.lu.se/record/4bae637a-06af-4311-ad58-9cb5b8171c21URI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:143498372URI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Vallin, Karl S.Karolinska Institute (författare)
  • Bräutigam, LarsKarolinska Institutet (författare)
  • Sarno, AntonioKarolinska Institutet (författare)
  • Warpman Berglund, UlrikaKarolinska Institutet,Karolinska Institute (författare)
  • Helleday, ThomasKarolinska Institutet (författare)
  • Stenmark, PålStockholm University,Lunds universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Lund University, Sweden,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Strukturell biokemi,Forskargrupper vid Lunds universitet,Department of Experimental Medical Science,Faculty of Medicine,Structural Biochemistry,Lund University Research Groups(Swepub:lu)pa4463st (författare)
  • Jemth, Ann-SofieKarolinska Institute (författare)
  • Stockholms universitetInstitutionen för biokemi och biofysik (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Journal of Biological Chemistry295:15, s. 4761-47720021-92581083-351X

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