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PMID: 18775698 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO.

FEBS letters ·Vol. 582 ·No. 23-24 ·2008-10-15 ·Pages 3313-9

Jia G, Yang CG, Yang S, Jian X, Yi C, Zhou Z, He C

Abstract

The human obesity susceptibility gene, FTO, encodes a protein that is homologous to the DNA repair AlkB protein. The AlkB family proteins utilize iron(II), alpha-ketoglutarate (alpha-KG) and dioxygen to perform oxidative repair of alkylated nucleobases in DNA and RNA. We demonstrate here the oxidative demethylation of 3-methylthymine (3-meT) in single-stranded DNA (ssDNA) and 3-methyluracil (3-meU) in single-stranded RNA (ssRNA) by recombinant human FTO protein in vitro. Both human and mouse FTO proteins preferentially repair 3-meT in ssDNA over other base lesions tested. They showed negligible activities against 3-meT in double-stranded DNA (dsDNA). In addition, these two proteins can catalyze the demethylation of 3-meU in ssRNA with a slightly higher efficiency over that of 3-meT in ssDNA, suggesting that methylated RNAs are the preferred substrates for FTO.

MeSH Terms
Alpha-Ketoglutarate-Dependent Dioxygenase FTO Animals DNA Repair DNA, Single-Stranded/chemistry,metabolism Humans Methylation Mice Mixed Function Oxygenases Oxidation-Reduction Oxo-Acid-Lyases/chemistry,metabolism Proteins/chemistry,metabolism RNA/metabolism Recombinant Proteins/chemistry Substrate Specificity Thymine/analogs & derivatives,chemistry,metabolism Uracil/analogs & derivatives,chemistry,metabolism
Chemicals
DNA, Single-Stranded Proteins Recombinant Proteins Uracil 3-methyluracil RNA Mixed Function Oxygenases FTO protein, mouse Alpha-Ketoglutarate-Dependent Dioxygenase FTO FTO protein, human Oxo-Acid-Lyases Thymine 3-methylthymine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Jia Guifang
Department of Chemistry, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
Yang Cai-Guang
Yang Shangdong
Jian Xing
Yi Chengqi
Zhou Zhiqiang
He Chuan
References (29)
29 references, click to expand
  1. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.
    Science. 2007 Jun 1;316(5829):1341-5 PMID: 17463248
  2. Phylogenomic identification of five new human homologs of the DNA repair enzyme AlkB.
    BMC Genomics. 2003 Dec 10;4(1):48 PMID: 14667252
  3. Direct reversal of DNA alkylation damage.
    Chem Rev. 2006 Feb;106(2):215-32 PMID: 16464003
  4. Repair of methylation damage in DNA and RNA by mammalian AlkB homologues.
    J Biol Chem. 2005 Nov 25;280(47):39448-59 PMID: 16174769
  5. Reversal of DNA alkylation damage by two human dioxygenases.
    Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16660-5 PMID: 12486230
  6. Oxidative dealkylation DNA repair mediated by the mononuclear non-heme iron AlkB proteins.
    J Inorg Biochem. 2006 Apr;100(4):670-8 PMID: 16469386
  7. Incorporation of oxygen into the succinate co-product of iron(II) and 2-oxoglutarate dependent oxygenases from bacteria, plants and humans.
    FEBS Lett. 2005 Sep 26;579(23):5170-4 PMID: 16153644
  8. Repair of alkylated DNA: recent advances.
    DNA Repair (Amst). 2007 Apr 1;6(4):429-42 PMID: 17112791
  9. The selectivity and inhibition of AlkB.
    J Biol Chem. 2003 Mar 21;278(12):10157-61 PMID: 12517755
  10. Direct repair of the exocyclic DNA adduct 1,N6-ethenoadenine by the DNA repair AlkB proteins.
    J Am Chem Soc. 2005 Oct 26;127(42):14594-5 PMID: 16231911
  11. Substrate specificities of bacterial and human AlkB proteins.
    Nucleic Acids Res. 2004 Jun 30;32(11):3456-61 PMID: 15229293
  12. The FTO gene, implicated in human obesity, is found only in vertebrates and marine algae.
    J Mol Evol. 2008 Jan;66(1):80-4 PMID: 18058156
  13. Repair of 3-methylthymine and 1-methylguanine lesions by bacterial and human AlkB proteins.
    Nucleic Acids Res. 2004 Dec 01;32(21):6260-7 PMID: 15576352
  14. Preparation and enzymatic hydrolysis of DNA and RNA for mass spectrometry.
    Methods Enzymol. 1990;193:782-90 PMID: 1706062
  15. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.
    Science. 2007 May 11;316(5826):889-94 PMID: 17434869
  16. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA.
    Nature. 2003 Feb 20;421(6925):859-63 PMID: 12594517
  17. AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli.
    Nature. 2002 Sep 12;419(6903):178-82 PMID: 12226668
  18. Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB.
    Nature. 2006 Feb 16;439(7078):879-84 PMID: 16482161
  19. Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage.
    Nature. 2002 Sep 12;419(6903):174-8 PMID: 12226667
  20. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.
    Science. 2007 Nov 30;318(5855):1469-72 PMID: 17991826
  21. Expression and sub-cellular localization of human ABH family molecules.
    J Cell Mol Med. 2007 Sep-Oct;11(5):1105-16 PMID: 17979886
  22. Repair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA.
    EMBO J. 2006 May 17;25(10):2189-98 PMID: 16642038
  23. The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily.
    BMC Biochem. 2007 Nov 08;8:23 PMID: 17996046
  24. Variation in FTO contributes to childhood obesity and severe adult obesity.
    Nat Genet. 2007 Jun;39(6):724-6 PMID: 17496892
  25. AlkB homologue 2-mediated repair of ethenoadenine lesions in mammalian DNA.
    Cancer Res. 2008 Jun 1;68(11):4142-9 PMID: 18519673
  26. AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo.
    Nat Struct Mol Biol. 2005 Oct;12(10):855-60 PMID: 16200073
  27. Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA.
    Nature. 2008 Apr 24;452(7190):961-5 PMID: 18432238
  28. Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli.
    Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14051-6 PMID: 15381779
  29. Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage.
    EMBO J. 2006 Jul 26;25(14):3389-97 PMID: 16858410
Article Info
Journal
FEBS letters
Abbr.
FEBS Lett
ISSN
0014-5793
DOI
10.1016/j.febslet.2008.08.019
Published
2008-10-15
Epub
2008-00-05
Pages
3313-9
Language
English
Region
England
NLM ID
0155157
PMCID
PMC2577709
Subset
IM
Grants
NIGMS NIH HHS · R01 GM071440 · United States
NIGMS NIH HHS · R01 GM071440-04 · United States
NIGMS NIH HHS · GM071440 · United States
External Links
PubMed source DOI: 10.1016/j.febslet.2008.08.019 PMC Full Text View journal details
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