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

The Journal of Biological Chemistry
Emma Rose ScalettiAnn-Sofie Jemth

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...Continue Reading

References

Nov 9, 1994·Molecular and Cellular Biochemistry·T W Traut
Jul 1, 1995·Developmental Dynamics : an Official Publication of the American Association of Anatomists·C B KimmelT F Schilling
Jun 22, 1999·The Journal of Biological Chemistry·K FujikawaH Kasai
Mar 18, 2000·The Journal of Biological Chemistry·H YangJ H Miller
Jan 5, 2001·Nucleic Acids Research·K FujikawaH Kasai
Sep 27, 2001·Proceedings of the National Academy of Sciences of the United States of America·T TsuzukiM Sekiguchi
Jul 15, 2003·The Journal of Biological Chemistry·Daisuke YoshimuraYusaku Nakabeppu
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Dec 22, 2005·Acta Crystallographica. Section D, Biological Crystallography·Philip Evans
Dec 27, 2005·Cellular and Molecular Life Sciences : CMLS·A G McLennan
Feb 21, 2006·Nature Reviews. Microbiology·Didier Wion, Josep Casadesús
Mar 4, 2006·Biochemical Pharmacology·Markéta SchinkmanováAntonín Holý
Oct 28, 2006·Journal of Experimental Zoology. Part B, Molecular and Developmental Evolution·John H Postlethwait
Nov 22, 2008·Science·John EidStephen Turner
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Nov 10, 2009·Biochemical and Biophysical Research Communications·Candy A HeyenPeter J Roach
Jul 27, 2011·FEBS Letters·Linda M SvenssonPål Stenmark
Apr 18, 2013·The Journal of Biological Chemistry·Josep Casadesús, David A Low
Apr 10, 2014·Nature Reviews. Molecular Cell Biology·Kate D Meyer, Samie R Jaffrey
May 6, 2015·Cell·Holger Heyn, Manel Esteller
May 6, 2015·Cell·Guoqiang ZhangDahua Chen
May 6, 2015·Cell·Eric Lieberman GreerYang Shi
Oct 29, 2015·Nature Reviews. Molecular Cell Biology·Guan-Zheng LuoYang Shi
Feb 18, 2016·Journal of Medicinal Chemistry·Jason G KettleMarta Wylot
Nov 9, 2016·Annals of Oncology : Official Journal of the European Society for Medical Oncology·U Warpman BerglundT Helleday
Dec 17, 2016·Journal of Applied Crystallography·James M ParkhurstGwyndaf Evans
Apr 22, 2017·Nucleic Acids Research·Szymon ChojnackiRodrigo Lopez
Nov 17, 2017·Nature Communications·Jordi Carreras-PuigvertThomas Helleday
Dec 24, 2017·Scientific Reports·Stacey L KigarAnthony P Auger
Jul 19, 2018·Molecular Cell·Chuan-Le XiaoGuang-Rong Yan
Nov 6, 2018·Cell·Qi XieJeremy N Rich

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Citations

Nov 28, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Matthias Bochtler, Humberto Fernandes
Feb 14, 2021·Redox Biology·Mu-Rong ChaoMarcus S Cooke

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