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PMID: 26152727 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond.

The Journal of biological chemistry ·Vol. 290 ·No. 34 ·2015-08-21 ·Pages 20734-20742

Fedeles BI, Singh V, Delaney JC, Li D, Essigmann JM

Abstract

The AlkB family of Fe(II)- and α-ketoglutarate-dependent dioxygenases is a class of ubiquitous direct reversal DNA repair enzymes that remove alkyl adducts from nucleobases by oxidative dealkylation. The prototypical and homonymous family member is an Escherichia coli "adaptive response" protein that protects the bacterial genome against alkylation damage. AlkB has a wide variety of substrates, including monoalkyl and exocyclic bridged adducts. Nine mammalian AlkB homologs exist (ALKBH1-8, FTO), but only a subset functions as DNA/RNA repair enzymes. This minireview presents an overview of the AlkB proteins including recent data on homologs, structural features, substrate specificities, and experimental strategies for studying DNA repair by AlkB family proteins.

Keywords
DNA demethylation DNA repair RNA demethylation RNA repair alkB alkylation damage dioxygenase direct reversal metalloprotein substrate specificity
MeSH Terms
AlkB Homolog 4, Lysine Demethylase Alkylation DNA Damage DNA Repair DNA, Single-Stranded/genetics,metabolism Dioxygenases/genetics,metabolism Escherichia coli/enzymology,genetics Escherichia coli Proteins/genetics,metabolism Gene Expression Humans Iron/metabolism Isoenzymes/genetics,metabolism Ketoglutaric Acids/metabolism Mixed Function Oxygenases/genetics,metabolism Models, Molecular Multigene Family Oxidation-Reduction Substrate Specificity
Chemicals
DNA, Single-Stranded Escherichia coli Proteins Isoenzymes Ketoglutaric Acids Iron Mixed Function Oxygenases Dioxygenases AlkB protein, E coli ALKBH4 protein, human AlkB Homolog 4, Lysine Demethylase
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Fedeles Bogdan I
Departments of Chemistry and Biological Engineering and the Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
Singh Vipender
Departments of Chemistry and Biological Engineering and the Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
Delaney James C
Departments of Chemistry and Biological Engineering and the Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
Li Deyu
Departments of Chemistry and Biological Engineering and the Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139. Electronic address: deyuli@uri.edu.
Essigmann John M
Departments of Chemistry and Biological Engineering and the Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139. Electronic address: jessig@mit.edu.
References (97)
97 references, click to expand
  1. Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1α (HIF-1α).
    PLoS One. 2011;6(1):e16210 PMID: 21264265
  2. Crystal structure and RNA binding properties of the RNA recognition motif (RRM) and AlkB domains in human AlkB homolog 8 (ABH8), an enzyme catalyzing tRNA hypermodification.
    J Biol Chem. 2012 Jan 13;287(3):2130-43 PMID: 22065580
  3. Theory uncovers an unusual mechanism of DNA repair of a lesioned adenine by AlkB enzymes.
    J Am Chem Soc. 2014 Oct 1;136(39):13895-901 PMID: 25203306
  4. Kinetic and spectroscopic investigation of CoII, NiII, and N-oxalylglycine inhibition of the FeII/alpha-ketoglutarate dioxygenase, TauD.
    Biochem Biophys Res Commun. 2005 Dec 9;338(1):191-7 PMID: 16165092
  5. Chloroacetaldehyde-induced mutagenesis in Escherichia coli: the role of AlkB protein in repair of 3,N(4)-ethenocytosine and 3,N(4)-alpha-hydroxyethanocytosine.
    Mutat Res. 2010 Feb 3;684(1-2):24-34 PMID: 19941873
  6. Crystal structures of the human RNA demethylase Alkbh5 reveal basis for substrate recognition.
    J Biol Chem. 2014 Apr 25;289(17):11571-83 PMID: 24616105
  7. Repair of methyl lesions in DNA and RNA by oxidative demethylation.
    Neuroscience. 2007 Apr 14;145(4):1222-32 PMID: 17175108
  8. Dynamic combinatorial mass spectrometry leads to inhibitors of a 2-oxoglutarate-dependent nucleic acid demethylase.
    J Med Chem. 2012 Mar 8;55(5):2173-84 PMID: 22263962
  9. Alleviation of 1,N6-ethanoadenine genotoxicity by the Escherichia coli adaptive response protein AlkB.
    Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):755-60 PMID: 17213319
  10. Protozoan ALKBH8 oxygenases display both DNA repair and tRNA modification activities.
    PLoS One. 2014;9(6):e98729 PMID: 24914785
  11. Bioinformatics and functional analysis define four distinct groups of AlkB DNA-dioxygenases in bacteria.
    Nucleic Acids Res. 2009 Nov;37(21):7124-36 PMID: 19786499
  12. Human ALKBH7 is required for alkylation and oxidation-induced programmed necrosis.
    Genes Dev. 2013 May 15;27(10):1089-100 PMID: 23666923
  13. Mechanism and function of oxidative reversal of DNA and RNA methylation.
    Annu Rev Biochem. 2014;83:585-614 PMID: 24905787
  14. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.
    Nat Chem Biol. 2011 Dec;7(12):885-7 PMID: 22002720
  15. L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer.
    Cancer Discov. 2014 Nov;4(11):1290-8 PMID: 25182153
  16. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.
    Mol Cell. 2013 Jan 10;49(1):18-29 PMID: 23177736
  17. The Escherichia coli AlkB protein protects human cells against alkylation-induced toxicity.
    J Bacteriol. 1994 Oct;176(20):6255-61 PMID: 7928996
  18. Demethylation of 3-methylthymine in DNA by bacterial and human DNA dioxygenases.
    J Biol Chem. 2004 Sep 24;279(39):40470-4 PMID: 15269201
  19. FTO gene variant and risk of overweight and obesity among children and adolescents: a systematic review and meta-analysis.
    PLoS One. 2013;8(11):e82133 PMID: 24278475
  20. Removal of N-alkyl modifications from N(2)-alkylguanine and N(4)-alkylcytosine in DNA by the adaptive response protein AlkB.
    Chem Res Toxicol. 2013 Aug 19;26(8):1182-7 PMID: 23773213
  21. AlkB restores the biological function of mRNA and tRNA inactivated by chemical methylation.
    Mol Cell. 2004 Oct 8;16(1):107-16 PMID: 15469826
  22. DFT study of a model system for the dealkylation step catalyzed by AlkB.
    Interdiscip Sci. 2010 Mar;2(1):70-7 PMID: 20640798
  23. Mechanistic insight into the recognition of single-stranded and double-stranded DNA substrates by ABH2 and ABH3.
    Mol Biosyst. 2010 Nov;6(11):2143-9 PMID: 20714506
  24. Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA.
    Nature. 2008 Apr 24;452(7190):961-5 PMID: 18432238
  25. Human AlkB homolog ABH8 Is a tRNA methyltransferase required for wobble uridine modification and DNA damage survival.
    Mol Cell Biol. 2010 May;30(10):2449-59 PMID: 20308323
  26. Repairing DNA-methylation damage.
    Nat Rev Mol Cell Biol. 2004 Feb;5(2):148-57 PMID: 15040447
  27. Pediatric brain tumors: mutations of two dioxygenases (hABH2 and hABH3) that directly repair alkylation damage.
    J Neurooncol. 2009 Sep;94(2):195-201 PMID: 19290481
  28. Human AlkB homolog 1 is a mitochondrial protein that demethylates 3-methylcytosine in DNA and RNA.
    J Biol Chem. 2008 Sep 5;283(36):25046-56 PMID: 18603530
  29. Alkbh2 protects against lethality and mutation in primary mouse embryonic fibroblasts.
    DNA Repair (Amst). 2012 May 1;11(5):502-10 PMID: 22429847
  30. Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage.
    Nature. 2002 Sep 12;419(6903):174-8 PMID: 12226667
  31. Viral AlkB proteins repair RNA damage by oxidative demethylation.
    Nucleic Acids Res. 2008 Oct;36(17):5451-61 PMID: 18718927
  32. Alkylation damage in DNA and RNA--repair mechanisms and medical significance.
    DNA Repair (Amst). 2004 Nov 2;3(11):1389-407 PMID: 15380096
  33. 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
  34. Structure and function of DNA methyltransferases.
    Annu Rev Biophys Biomol Struct. 1995;24:293-318 PMID: 7663118
  35. Iron-catalysed oxidation intermediates captured in a DNA repair dioxygenase.
    Nature. 2010 Nov 11;468(7321):330-3 PMID: 21068844
  36. Mechanism of repair of acrolein- and malondialdehyde-derived exocyclic guanine adducts by the α-ketoglutarate/Fe(II) dioxygenase AlkB.
    Chem Res Toxicol. 2014 Sep 15;27(9):1619-31 PMID: 25157679
  37. Spectroscopic and magnetic studies of wild-type and mutant forms of the Fe(II)- and 2-oxoglutarate-dependent decarboxylase ALKBH4.
    Biochem J. 2011 Mar 15;434(3):391-8 PMID: 21166655
  38. Substrate specificities of bacterial and human AlkB proteins.
    Nucleic Acids Res. 2004;32(11):3456-61 PMID: 15229293
  39. Impaired placental trophoblast lineage differentiation in Alkbh1(-/-) mice.
    Dev Dyn. 2008 Feb;237(2):316-27 PMID: 18163532
  40. DNA demethylation, Tet proteins and 5-hydroxymethylcytosine in epigenetic reprogramming: an emerging complex story.
    Genomics. 2014 Nov;104(5):324-33 PMID: 25173569
  41. Herbicide-degrading alpha-keto acid-dependent enzyme TfdA: metal coordination environment and mechanistic insights.
    Biochemistry. 1999 Dec 14;38(50):16714-26 PMID: 10600135
  42. Crystal structure of the FTO protein reveals basis for its substrate specificity.
    Nature. 2010 Apr 22;464(7292):1205-9 PMID: 20376003
  43. Homology modeling, molecular dynamics, and site-directed mutagenesis study of AlkB human homolog 1 (ALKBH1).
    J Mol Graph Model. 2014 Nov;54:123-30 PMID: 25459764
  44. Decreased N(6)-methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5.
    J Clin Endocrinol Metab. 2015 Jan;100(1):E148-54 PMID: 25303482
  45. Advances in chemical carcinogenesis: a historical review and prospective.
    Cancer Res. 2008 Sep 1;68(17):6863-72 PMID: 18757397
  46. Chemical biology of mutagenesis and DNA repair: cellular responses to DNA alkylation.
    Carcinogenesis. 2010 Jan;31(1):59-70 PMID: 19875697
  47. 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
  48. AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli.
    Nature. 2002 Sep 12;419(6903):178-82 PMID: 12226668
  49. DNA repair by reversal of DNA damage.
    Cold Spring Harb Perspect Biol. 2013 Jan;5(1):a012575 PMID: 23284047
  50. Rapid freeze-quench 57Fe Mössbauer spectroscopy: monitoring changes of an iron-containing active site during a biochemical reaction.
    Inorg Chem. 2005 Feb 21;44(4):742-57 PMID: 15859243
  51. ALKBH1 is a histone H2A dioxygenase involved in neural differentiation.
    Stem Cells. 2012 Dec;30(12):2672-82 PMID: 22961808
  52. A covalent protein-DNA 5'-product adduct is generated following AP lyase activity of human ALKBH1 (AlkB homologue 1).
    Biochem J. 2013 Jun 15;452(3):509-18 PMID: 23577621
  53. Frequent down-regulation of hABH2 in gastric cancer and its involvement in growth of cancer cells.
    J Gastroenterol Hepatol. 2011 Mar;26(3):577-84 PMID: 21155885
  54. Alternative Pathway for the Reaction Catalyzed by DNA Dealkylase AlkB from Ab Initio QM/MM Calculations.
    J Chem Theory Comput. 2014 Nov 11;10(11):5136-5148 PMID: 25400523
  55. ABH2 couples regulation of ribosomal DNA transcription with DNA alkylation repair.
    Cell Rep. 2013 Aug 29;4(4):817-29 PMID: 23972994
  56. Role of the N6-methyladenosine RNA mark in gene regulation and its implications on development and disease.
    Brief Funct Genomics. 2015 May;14(3):169-79 PMID: 25305461
  57. Switching demethylation activities between AlkB family RNA/DNA demethylases through exchange of active-site residues.
    Angew Chem Int Ed Engl. 2014 Apr 1;53(14):3659-62 PMID: 24596302
  58. The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases.
    Genome Biol. 2001;2(3):RESEARCH0007 PMID: 11276424
  59. Next-generation sequencing reveals the biological significance of the N(2),3-ethenoguanine lesion in vivo.
    Nucleic Acids Res. 2015 Jun 23;43(11):5489-500 PMID: 25837992
  60. ALKBH4-dependent demethylation of actin regulates actomyosin dynamics.
    Nat Commun. 2013;4:1832 PMID: 23673617
  61. The AlkB domain of mammalian ABH8 catalyzes hydroxylation of 5-methoxycarbonylmethyluridine at the wobble position of tRNA.
    Angew Chem Int Ed Engl. 2010 Nov 15;49(47):8885-8 PMID: 20583019
  62. Mechanistic studies on the application of DNA aptamers as inhibitors of 2-oxoglutarate-dependent oxygenases.
    J Med Chem. 2012 Apr 12;55(7):3546-52 PMID: 22471443
  63. The Schizosaccharomyces pombe AlkB homolog Abh1 exhibits AP lyase activity but no demethylase activity.
    DNA Repair (Amst). 2012 May 1;11(5):453-62 PMID: 22365419
  64. Enzymological and structural studies of the mechanism of promiscuous substrate recognition by the oxidative DNA repair enzyme AlkB.
    Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14315-20 PMID: 19706517
  65. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes.
    Curr Opin Struct Biol. 1999 Dec;9(6):722-31 PMID: 10607676
  66. ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA.
    Nat Commun. 2011;2:172 PMID: 21285950
  67. Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation.
    J Biol Chem. 2014 Jun 20;289(25):17299-311 PMID: 24778178
  68. 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
  69. Non-heme Fe(IV)-oxo intermediates.
    Acc Chem Res. 2007 Jul;40(7):484-92 PMID: 17542550
  70. anti-tumor effect of AlkB homolog 3 knockdown in hormone- independent prostate cancer cells.
    Curr Cancer Drug Targets. 2012 Sep;12(7):847-56 PMID: 22515525
  71. ALKBH1 is dispensable for abasic site cleavage during base excision repair and class switch recombination.
    PLoS One. 2013;8(6):e67403 PMID: 23825659
  72. DNA methylation in thermophilic bacteria: N4-methylcytosine, 5-methylcytosine, and N6-methyladenine.
    Nucleic Acids Res. 1985 Feb 25;13(4):1399-412 PMID: 4000939
  73. Deletion of mouse Alkbh7 leads to obesity.
    J Mol Cell Biol. 2013 Jun;5(3):194-203 PMID: 23572141
  74. Mice lacking Alkbh1 display sex-ratio distortion and unilateral eye defects.
    PLoS One. 2010;5(11):e13827 PMID: 21072209
  75. Differential repair of etheno-DNA adducts by bacterial and human AlkB proteins.
    DNA Repair (Amst). 2015 Jun;30:1-10 PMID: 25797601
  76. A DFT study of nucleobase dealkylation by the DNA repair enzyme AlkB.
    J Phys Chem B. 2009 Apr 9;113(14):4887-98 PMID: 19338370
  77. The atomic resolution structure of human AlkB homolog 7 (ALKBH7), a key protein for programmed necrosis and fat metabolism.
    J Biol Chem. 2014 Oct 3;289(40):27924-36 PMID: 25122757
  78. Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA.
    Nature. 2003 Feb 20;421(6925):859-63 PMID: 12594517
  79. A chemical genetics analysis of the roles of bypass polymerase DinB and DNA repair protein AlkB in processing N2-alkylguanine lesions in vivo.
    PLoS One. 2014;9(4):e94716 PMID: 24733044
  80. The dynamic epitranscriptome: N6-methyladenosine and gene expression control.
    Nat Rev Mol Cell Biol. 2014 May;15(5):313-26 PMID: 24713629
  81. Repair of DNA Alkylation Damage by the Escherichia coli Adaptive Response Protein AlkB as Studied by ESI-TOF Mass Spectrometry.
    J Nucleic Acids. 2010 Oct 27;2010:369434 PMID: 21048928
  82. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO.
    FEBS Lett. 2008 Oct 15;582(23-24):3313-9 PMID: 18775698
  83. Assays for determining lesion bypass efficiency and mutagenicity of site-specific DNA lesions in vivo.
    Methods Enzymol. 2006;408:1-15 PMID: 16793359
  84. Repair of alkylated DNA: recent advances.
    DNA Repair (Amst). 2007 Apr 1;6(4):429-42 PMID: 17112791
  85. 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
  86. AlkB dioxygenase preferentially repairs protonated substrates: specificity against exocyclic adducts and molecular mechanism of action.
    J Biol Chem. 2013 Jan 4;288(1):432-41 PMID: 23148216
  87. DNA repair is indispensable for survival after acute inflammation.
    J Clin Invest. 2012 Jul;122(7):2680-9 PMID: 22684101
  88. Exocyclic carbons adjacent to the N6 of adenine are targets for oxidation by the Escherichia coli adaptive response protein AlkB.
    J Am Chem Soc. 2012 May 30;134(21):8896-901 PMID: 22512456
  89. FTO and obesity: mechanisms of association.
    Curr Diab Rep. 2014;14(5):486 PMID: 24627050
  90. 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
  91. Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB.
    Nature. 2006 Feb 16;439(7078):879-84 PMID: 16482161
  92. 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
  93. DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation.
    Mol Cell. 2011 Nov 4;44(3):373-84 PMID: 22055184
  94. Overexpression of Fto leads to increased food intake and results in obesity.
    Nat Genet. 2010 Dec;42(12):1086-92 PMID: 21076408
  95. Structure and mechanism of anthocyanidin synthase from Arabidopsis thaliana.
    Structure. 2002 Jan;10(1):93-103 PMID: 11796114
  96. Direct repair of 3,N(4)-ethenocytosine by the human ALKBH2 dioxygenase is blocked by the AAG/MPG glycosylase.
    DNA Repair (Amst). 2012 Jan 2;11(1):46-52 PMID: 22079122
  97. A new pathway for DNA repair in Escherichia coli.
    Nature. 1977 May 19;267(5608):281-3 PMID: 325420
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.R115.656462
Email
deyuli@uri.edu
jessig@mit.edu
Published
2015-08-21
Epub
2015-00-07
Pages
20734-20742
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC4543635
Subset
IM
Grants
NCI NIH HHS · R37 CA080024 · United States
NCI NIH HHS · P01 CA26731 · United States
NIEHS NIH HHS · T32 ES007020 · United States
NIEHS NIH HHS · P30 ES002109 · United States
NCI NIH HHS · P01 CA026731 · United States
NCI NIH HHS · R01 CA080024 · United States
Databases
PDB
3O1P
External Links
PubMed source DOI: 10.1074/jbc.R115.656462 PMC Full Text View journal details
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