DNA Damage Reversal (Homo sapiens)

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2221222nucleoplasm6-O-methyguaninecontaining damagedDNACH3CHOSUCCAMGMT2OGAlkylated DNA with1-methyladenineCO2ALKBH2O2Alkylated DNA with1-ethyladenineDNA with no6-O-methylatedguanineAlkylated DNA with3-methylcytosineRepaired DNA afteroxidativedealkylationMetC-MGMTALKBH3CH2O


Description

DNA damage can be directly reversed by dealkylation.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=73942

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Ontology Terms

 

Bibliography

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  1. Duguid EM, Rice PA, He C.; ''The structure of the human AGT protein bound to DNA and its implications for damage detection.''; PubMed Europe PMC
  2. Tubbs JL, Pegg AE, Tainer JA.; ''DNA binding, nucleotide flipping, and the helix-turn-helix motif in base repair by O6-alkylguanine-DNA alkyltransferase and its implications for cancer chemotherapy.''; PubMed Europe PMC
  3. Rasimas JJ, Dalessio PA, Ropson IJ, Pegg AE, Fried MG.; ''Active-site alkylation destabilizes human O6-alkylguanine DNA alkyltransferase.''; PubMed Europe PMC
  4. Dango S, Mosammaparast N, Sowa ME, Xiong LJ, Wu F, Park K, Rubin M, Gygi S, Harper JW, Shi Y.; ''DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation.''; PubMed Europe PMC
  5. Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C.; ''N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.''; PubMed Europe PMC
  6. Feng C, Liu Y, Wang G, Deng Z, Zhang Q, Wu W, Tong Y, Cheng C, Chen Z.; ''Crystal structures of the human RNA demethylase Alkbh5 reveal basis for substrate recognition.''; PubMed Europe PMC
  7. Vora RA, Pegg AE, Ealick SE.; ''A new model for how O6-methylguanine-DNA methyltransferase binds DNA.''; PubMed Europe PMC
  8. Daniels DS, Mol CD, Arvai AS, Kanugula S, Pegg AE, Tainer JA.; ''Active and alkylated human AGT structures: a novel zinc site, inhibitor and extrahelical base binding.''; PubMed Europe PMC
  9. Duncan T, Trewick SC, Koivisto P, Bates PA, Lindahl T, Sedgwick B.; ''Reversal of DNA alkylation damage by two human dioxygenases.''; PubMed Europe PMC
  10. Merkestein M, Sellayah D.; ''Role of FTO in Adipocyte Development and Function: Recent Insights.''; PubMed Europe PMC
  11. Mitra S, Kaina B.; ''Regulation of repair of alkylation damage in mammalian genomes.''; PubMed Europe PMC
  12. Trewick SC, Henshaw TF, Hausinger RP, Lindahl T, Sedgwick B.; ''Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage.''; PubMed Europe PMC
  13. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD, Hattersley AT, McCarthy MI.; ''A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.''; PubMed Europe PMC
  14. Xu C, Liu K, Tempel W, Demetriades M, Aik W, Schofield CJ, Min J.; ''Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation.''; PubMed Europe PMC
  15. Moore MH, Gulbis JM, Dodson EJ, Demple B, Moody PC.; ''Crystal structure of a suicidal DNA repair protein: the Ada O6-methylguanine-DNA methyltransferase from E. coli.''; PubMed Europe PMC
  16. Aas PA, Otterlei M, Falnes PO, Vågbø CB, Skorpen F, Akbari M, Sundheim O, Bjørås M, Slupphaug G, Seeberg E, Krokan HE.; ''Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA.''; PubMed Europe PMC
  17. Zhao X, Yang Y, Sun BF, Zhao YL, Yang YG.; ''FTO and obesity: mechanisms of association.''; PubMed Europe PMC
  18. Lindahl T, Demple B, Robins P.; ''Suicide inactivation of the E. coli O6-methylguanine-DNA methyltransferase.''; PubMed Europe PMC
  19. Han Z, Niu T, Chang J, Lei X, Zhao M, Wang Q, Cheng W, Wang J, Feng Y, Chai J.; ''Crystal structure of the FTO protein reveals basis for its substrate specificity.''; PubMed Europe PMC
  20. Sundheim O, Vågbø CB, Bjørås M, Sousa MM, Talstad V, Aas PA, Drabløs F, Krokan HE, Tainer JA, Slupphaug G.; ''Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage.''; PubMed Europe PMC
  21. Chen B, Liu H, Sun X, Yang CG.; ''Mechanistic insight into the recognition of single-stranded and double-stranded DNA substrates by ABH2 and ABH3.''; PubMed Europe PMC
  22. Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, Carlsson LM, Kiess W, Vatin V, Lecoeur C, Delplanque J, Vaillant E, Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N, Hercberg S, Le Stunff C, Bougnères P, Kovacs P, Marre M, Balkau B, Cauchi S, Chèvre JC, Froguel P.; ''Variation in FTO contributes to childhood obesity and severe adult obesity.''; PubMed Europe PMC
  23. Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vågbø CB, Shi Y, Wang WL, Song SH, Lu Z, Bosmans RP, Dai Q, Hao YJ, Yang X, Zhao WM, Tong WM, Wang XJ, Bogdan F, Furu K, Fu Y, Jia G, Zhao X, Liu J, Krokan HE, Klungland A, Yang YG, He C.; ''ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101542view11:40, 1 November 2018ReactomeTeamreactome version 66
101077view21:23, 31 October 2018ReactomeTeamreactome version 65
100607view19:57, 31 October 2018ReactomeTeamreactome version 64
100158view16:42, 31 October 2018ReactomeTeamreactome version 63
99708view15:11, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99289view12:46, 31 October 2018ReactomeTeamreactome version 62
93865view13:41, 16 August 2017ReactomeTeamreactome version 61
93430view11:23, 9 August 2017ReactomeTeamreactome version 61
86521view09:20, 11 July 2016ReactomeTeamreactome version 56
83251view10:31, 18 November 2015ReactomeTeamVersion54
81358view12:53, 21 August 2015ReactomeTeamVersion53
76827view08:05, 17 July 2014ReactomeTeamFixed remaining interactions
76531view11:50, 16 July 2014ReactomeTeamFixed remaining interactions
75864view09:51, 11 June 2014ReactomeTeamRe-fixing comment source
75564view10:36, 10 June 2014ReactomeTeamReactome 48 Update
74919view13:44, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74563view08:36, 30 April 2014ReactomeTeamReactome46
69018view17:48, 8 July 2013MaintBotUpdated to 2013 gpml schema
45198view10:06, 7 October 2011MartijnVanIerselOntology Term : 'DNA repair pathway' added !
42027view21:51, 4 March 2011MaintBotAutomatic update
39830view05:51, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2OGMetaboliteCHEBI:30915 (ChEBI)
6-O-methyguanine

containing damaged

DNA
REACT_4587 (Reactome)
ALKBH2ProteinQ6NS38 (Uniprot-TrEMBL)
ALKBH3ProteinQ96Q83 (Uniprot-TrEMBL)
Alkylated DNA with 1-ethyladenineREACT_5603 (Reactome)
Alkylated DNA with 1-methyladenineREACT_3986 (Reactome)
Alkylated DNA with 3-methylcytosineREACT_4006 (Reactome)
CH2OMetaboliteCHEBI:16842 (ChEBI)
CH3CHOMetaboliteCHEBI:15343 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
DNA with no

6-O-methylated

guanine
REACT_4869 (Reactome)
MGMTProteinP16455 (Uniprot-TrEMBL)
MetC-MGMTProteinP16455 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
Repaired DNA after

oxidative

dealkylation
REACT_2610 (Reactome)
SUCCAMetaboliteCHEBI:15741 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2OGREACT_1435 (Reactome)
2OGREACT_1696 (Reactome)
2OGREACT_1934 (Reactome)
2OGREACT_2185 (Reactome)
2OGREACT_462 (Reactome)
2OGREACT_783 (Reactome)
6-O-methyguanine

containing damaged

DNA
REACT_1876 (Reactome)
ALKBH2mim-catalysisREACT_1696 (Reactome)
ALKBH2mim-catalysisREACT_2185 (Reactome)
ALKBH2mim-catalysisREACT_783 (Reactome)
ALKBH3mim-catalysisREACT_1435 (Reactome)
ALKBH3mim-catalysisREACT_1934 (Reactome)
ALKBH3mim-catalysisREACT_462 (Reactome)
Alkylated DNA with 1-ethyladenineREACT_1934 (Reactome)
Alkylated DNA with 1-ethyladenineREACT_783 (Reactome)
Alkylated DNA with 1-methyladenineREACT_1696 (Reactome)
Alkylated DNA with 1-methyladenineREACT_462 (Reactome)
Alkylated DNA with 3-methylcytosineREACT_1435 (Reactome)
Alkylated DNA with 3-methylcytosineREACT_2185 (Reactome)
CH2OArrowREACT_1435 (Reactome)
CH2OArrowREACT_1696 (Reactome)
CH2OArrowREACT_2185 (Reactome)
CH2OArrowREACT_462 (Reactome)
CH3CHOArrowREACT_1934 (Reactome)
CH3CHOArrowREACT_783 (Reactome)
CO2ArrowREACT_1435 (Reactome)
CO2ArrowREACT_1696 (Reactome)
CO2ArrowREACT_1934 (Reactome)
CO2ArrowREACT_2185 (Reactome)
CO2ArrowREACT_462 (Reactome)
CO2ArrowREACT_783 (Reactome)
DNA with no

6-O-methylated

guanine
ArrowREACT_1876 (Reactome)
MGMTREACT_1876 (Reactome)
MGMTmim-catalysisREACT_1876 (Reactome)
MetC-MGMTArrowREACT_1876 (Reactome)
O2REACT_1435 (Reactome)
O2REACT_1696 (Reactome)
O2REACT_1934 (Reactome)
O2REACT_2185 (Reactome)
O2REACT_462 (Reactome)
O2REACT_783 (Reactome)
REACT_1435 (Reactome) At the beginning of this reaction, 1 molecule of 'Alkylated DNA with 3-methylcytosine', 1 molecule of 'Oxygen', and 1 molecule of '2-Oxoglutarate' are present. At the end of this reaction, 1 molecule of 'Formaldehyde', 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', and 1 molecule of 'Succinate' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH3 protein'.

REACT_1696 (Reactome) At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of '2-Oxoglutarate', and 1 molecule of 'Alkylated DNA with 1-methyladenine' are present. At the end of this reaction, 1 molecule of 'Formaldehyde', 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', and 1 molecule of 'Succinate' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH2 protein'.

REACT_1876 (Reactome) Reactive cellular catabolites can cause DNA damage by 6-O-methylation of guanine. 6-O-methylguanine can pair ambiguously with both C and T, and can cause transition mutations. Active reversal of such damage can be facilitated by proteins having 6-O-methylguanine-DNA methyltransferase (MGMT) activity.

MGMT removes the methyl group from the guanine and transfers it to the cysteine residue at position 145 on the protein itself. MGMT thus methylated is not regenerated, as the S-methylcysteine is very stable. This is an energetically expensive approach to DNA repair as one entire protein molecule is sacrificed per lesion that is corrected in this manner (Yang et al. 2011).

REACT_1934 (Reactome) At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of 'Alkylated DNA with 1-ethyladenine', and 1 molecule of '2-Oxoglutarate' are present. At the end of this reaction, 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', 1 molecule of 'Succinate', and 1 molecule of 'Acetaldehyde' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH3 protein'.

REACT_2185 (Reactome) At the beginning of this reaction, 1 molecule of 'Alkylated DNA with 3-methylcytosine', 1 molecule of 'Oxygen', and 1 molecule of '2-Oxoglutarate' are present. At the end of this reaction, 1 molecule of 'Formaldehyde', 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', and 1 molecule of 'Succinate' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH2 protein'.

REACT_462 (Reactome) At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of '2-Oxoglutarate', and 1 molecule of 'Alkylated DNA with 1-methyladenine' are present. At the end of this reaction, 1 molecule of 'Formaldehyde', 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', and 1 molecule of 'Succinate' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH3 protein'.

REACT_783 (Reactome) At the beginning of this reaction, 1 molecule of 'Oxygen', 1 molecule of 'Alkylated DNA with 1-ethyladenine', and 1 molecule of '2-Oxoglutarate' are present. At the end of this reaction, 1 molecule of 'Repaired DNA after oxidative dealkylation', 1 molecule of 'CO2', 1 molecule of 'Succinate', and 1 molecule of 'Acetaldehyde' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'damaged DNA binding activity' of 'ABH2 protein'.

Repaired DNA after

oxidative

dealkylation
ArrowREACT_1435 (Reactome)
Repaired DNA after

oxidative

dealkylation
ArrowREACT_1696 (Reactome)
Repaired DNA after

oxidative

dealkylation
ArrowREACT_1934 (Reactome)
Repaired DNA after

oxidative

dealkylation
ArrowREACT_2185 (Reactome)
Repaired DNA after

oxidative

dealkylation
ArrowREACT_462 (Reactome)
Repaired DNA after

oxidative

dealkylation
ArrowREACT_783 (Reactome)
SUCCAArrowREACT_1435 (Reactome)
SUCCAArrowREACT_1696 (Reactome)
SUCCAArrowREACT_1934 (Reactome)
SUCCAArrowREACT_2185 (Reactome)
SUCCAArrowREACT_462 (Reactome)
SUCCAArrowREACT_783 (Reactome)
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