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

Research output: Contribution to journalArticle

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MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool. / Scaletti, Emma Rose; Vallin, Karl S; Bräutigam, Lars; Sarno, Antonio; Berglund, Ulrika Warpman; Helleday, Thomas; Stenmark, Pål; Jemth, Ann-Sofie.

In: Journal of Biological Chemistry, Vol. 295, No. 15, 2020, p. 4761-4772.

Research output: Contribution to journalArticle

Harvard

Scaletti, ER, Vallin, KS, Bräutigam, L, Sarno, A, Berglund, UW, Helleday, T, Stenmark, P & Jemth, A-S 2020, 'MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool', Journal of Biological Chemistry, vol. 295, no. 15, pp. 4761-4772. https://doi.org/10.1074/jbc.RA120.012636

APA

Scaletti, E. R., Vallin, K. S., Bräutigam, L., Sarno, A., Berglund, U. W., Helleday, T., Stenmark, P., & Jemth, A-S. (2020). MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool. Journal of Biological Chemistry, 295(15), 4761-4772. https://doi.org/10.1074/jbc.RA120.012636

CBE

Scaletti ER, Vallin KS, Bräutigam L, Sarno A, Berglund UW, Helleday T, Stenmark P, Jemth A-S. 2020. MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool. Journal of Biological Chemistry. 295(15):4761-4772. https://doi.org/10.1074/jbc.RA120.012636

MLA

Vancouver

Scaletti ER, Vallin KS, Bräutigam L, Sarno A, Berglund UW, Helleday T et al. MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool. Journal of Biological Chemistry. 2020;295(15):4761-4772. https://doi.org/10.1074/jbc.RA120.012636

Author

Scaletti, Emma Rose ; Vallin, Karl S ; Bräutigam, Lars ; Sarno, Antonio ; Berglund, Ulrika Warpman ; Helleday, Thomas ; Stenmark, Pål ; Jemth, Ann-Sofie. / MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool. In: Journal of Biological Chemistry. 2020 ; Vol. 295, No. 15. pp. 4761-4772.

RIS

TY - JOUR

T1 - MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool

AU - Scaletti, Emma Rose

AU - Vallin, Karl S

AU - Bräutigam, Lars

AU - Sarno, Antonio

AU - Berglund, Ulrika Warpman

AU - Helleday, Thomas

AU - Stenmark, Pål

AU - Jemth, Ann-Sofie

N1 - Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2020

Y1 - 2020

N2 - 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 sub-pocket 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.

AB - 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 sub-pocket 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.

U2 - 10.1074/jbc.RA120.012636

DO - 10.1074/jbc.RA120.012636

M3 - Article

C2 - 32144205

VL - 295

SP - 4761

EP - 4772

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 15

ER -