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MutT homologue 1 (M...
MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool
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- Scaletti, Emma Rose (författare)
- Stockholm 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
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- Vallin, Karl S. (författare)
- Karolinska Institute
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- Bräutigam, Lars (författare)
- Karolinska Institutet
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- Sarno, Antonio (författare)
- Karolinska Institutet
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- Warpman Berglund, Ulrika (författare)
- Karolinska Institutet,Karolinska Institute
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- Helleday, Thomas (författare)
- Karolinska Institutet
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- Stenmark, Pål (författare)
- Stockholm 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
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- Jemth, Ann-Sofie (författare)
- Karolinska Institute
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(creator_code:org_t)
- 2020
- 2020
- Engelska.
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 295:15, s. 4761-4772
- Relaterad länk:
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https://doi.org/10.1...
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http://dx.doi.org/10... (free)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Nyckelord
- crystal structure
- X-ray crystallography
- enzyme catalysis
- substrate specificity
- enzyme kinetics
- nucleoside
- nucleotide metabolism
- hydrolase
- epigenetics
- methylation
- MutT homologue 1 (MTH1)
- N6-methyl-dATP
- nucleotide hydrolysis
- Nudix hydrolase 1 (NUDT1)
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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