ID ALKB2_HUMAN Reviewed; 261 AA. AC Q6NS38; A4PET2; Q5XLE3; DT 30-MAY-2006, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 1. DT 24-JAN-2024, entry version 155. DE RecName: Full=DNA oxidative demethylase ALKBH2; DE EC=1.14.11.33 {ECO:0000269|PubMed:12486230, ECO:0000269|PubMed:16174769, ECO:0000269|PubMed:18432238, ECO:0000269|PubMed:20714506, ECO:0000269|PubMed:22659876}; DE AltName: Full=Alkylated DNA repair protein alkB homolog 2; DE AltName: Full=Alpha-ketoglutarate-dependent dioxygenase alkB homolog 2; DE AltName: Full=Oxy DC1; GN Name=ALKBH2; Synonyms=ABH2 {ECO:0000303|PubMed:16174769}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Lin Y., Xie Y., Mao Y.; RT "Cloning and expression of human 2OG-Fe(II) oxy DC1."; RL Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Testis; RX PubMed=17979886; DOI=10.1111/j.1582-4934.2007.00094.x; RA Tsujikawa K., Koike K., Kitae K., Shinkawa A., Arima H., Suzuki T., RA Tsuchiya M., Makino Y., Furukawa T., Konishi N., Yamamoto H.; RT "Expression and sub-cellular localization of human ABH family molecules."; RL J. Cell. Mol. Med. 11:1105-1116(2007). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION, RP AND TISSUE SPECIFICITY. RX PubMed=12486230; DOI=10.1073/pnas.262589799; RA Duncan T., Trewick S.C., Koivisto P., Bates P.A., Lindahl T., Sedgwick B.; RT "Reversal of DNA alkylation damage by two human dioxygenases."; RL Proc. Natl. Acad. Sci. U.S.A. 99:16660-16665(2002). RN [6] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=12594517; DOI=10.1038/nature01363; RA Aas P.A., Otterlei M., Falnes P.O., Vaagboe C.B., Skorpen F., Akbari M., RA Sundheim O., Bjoeraas M., Slupphaug G., Seeberg E., Krokan H.E.; RT "Human and bacterial oxidative demethylases repair alkylation damage in RT both RNA and DNA."; RL Nature 421:859-863(2003). RN [7] RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF RP ASP-173 AND HIS-236, AND TISSUE SPECIFICITY. RX PubMed=16174769; DOI=10.1074/jbc.m509881200; RA Lee D.-H., Jin S.-G., Cai S., Chen Y., Pfeifer G.P., O'Connor T.R.; RT "Repair of methylation damage in DNA and RNA by mammalian AlkB RT homologues."; RL J. Biol. Chem. 280:39448-39459(2005). RN [8] RP FUNCTION, ACTIVITY REGULATION, AND COFACTOR. RX PubMed=18519673; DOI=10.1158/0008-5472.can-08-0796; RA Ringvoll J., Moen M.N., Nordstrand L.M., Meira L.B., Pang B., Bekkelund A., RA Dedon P.C., Bjelland S., Samson L.D., Falnes P.O., Klungland A.; RT "AlkB homologue 2-mediated repair of ethenoadenine lesions in mammalian RT DNA."; RL Cancer Res. 68:4142-4149(2008). RN [9] RP FUNCTION, INTERACTION WITH PCNA, SUBCELLULAR LOCATION, MOTIF, AND RP MUTAGENESIS OF ARG-3; PHE-4; 5-LEU-VAL-6 AND LYS-7. RX PubMed=19736315; DOI=10.1083/jcb.200903138; RA Gilljam K.M., Feyzi E., Aas P.A., Sousa M.M., Mueller R., Vaagboe C.B., RA Catterall T.C., Liabakk N.B., Slupphaug G., Drabloes F., Krokan H.E., RA Otterlei M.; RT "Identification of a novel, widespread, and functionally important PCNA- RT binding motif."; RL J. Cell Biol. 186:645-654(2009). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF VAL-101; PHE-102; RP 101-VAL--GLY-103; ARG-110; TYR-122; PHE-124; SER-125 AND GLU-175. RX PubMed=20714506; DOI=10.1039/c005148a; RA Chen B., Liu H., Sun X., Yang C.G.; RT "Mechanistic insight into the recognition of single-stranded and double- RT stranded DNA substrates by ABH2 and ABH3."; RL Mol. Biosyst. 6:2143-2149(2010). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [12] RP FUNCTION, INTERACTION WITH NCL; NPM1; UBTF; PCNA AND XRCC5-XRCC6 COMPLEX, RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF 38-ARG--ARG-40 AND ASP-173. RX PubMed=23972994; DOI=10.1016/j.celrep.2013.07.027; RA Li P., Gao S., Wang L., Yu F., Li J., Wang C., Li J., Wong J.; RT "ABH2 couples regulation of ribosomal DNA transcription with DNA alkylation RT repair."; RL Cell Rep. 4:817-829(2013). RN [13] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=25797601; DOI=10.1016/j.dnarep.2015.02.021; RA Zdzalik D., Domanska A., Prorok P., Kosicki K., van den Born E., RA Falnes P.O., Rizzo C.J., Guengerich F.P., Tudek B.; RT "Differential repair of etheno-DNA adducts by bacterial and human AlkB RT proteins."; RL DNA Repair 30:1-10(2015). RN [14] RP FUNCTION, INTERACTION WITH PCNA, MUTAGENESIS OF PHE-4, AND VARIANTS VAL-9 RP AND LYS-10. RX PubMed=26408825; DOI=10.1016/j.dnarep.2015.09.008; RA Fu D., Samson L.D., Huebscher U., van Loon B.; RT "The interaction between ALKBH2 DNA repair enzyme and PCNA is direct, RT mediated by the hydrophobic pocket of PCNA and perturbed in naturally- RT occurring ALKBH2 variants."; RL DNA Repair 35:13-18(2015). RN [15] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 56-258 IN COMPLEXES WITH DS-DNA; RP 2-OXOGLUTARATE AND METAL IONS, FUNCTION, CATALYTIC ACTIVITY, AND COFACTOR. RX PubMed=18432238; DOI=10.1038/nature06889; RA Yang C.G., Yi C., Duguid E.M., Sullivan C.T., Jian X., Rice P.A., He C.; RT "Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to RT dsDNA."; RL Nature 452:961-965(2008). RN [16] RP X-RAY CRYSTALLOGRAPHY (1.77 ANGSTROMS) OF 56-261 IN COMPLEXES WITH RP DOUBLE-STRANDED DNA CONTAINING N1-METHYLADENINE OR N3-METHYLCYTOSINE. RX PubMed=20223766; DOI=10.1093/nar/gkq129; RA Lu L., Yi C., Jian X., Zheng G., He C.; RT "Structure determination of DNA methylation lesions N1-meA and N3-meC in RT duplex DNA using a cross-linked protein-DNA system."; RL Nucleic Acids Res. 38:4415-4425(2010). RN [17] RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 56-258 IN COMPLEX WITH RP 2-OXOGLUTARATE AND DOUBLE-STRANDED DNA CONTAINING N3-METHYLCYTOSINE OR RP 1,N6-ETHENOADENINE, FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF RP VAL-101 AND PHE-102. RX PubMed=22659876; DOI=10.1038/nsmb.2320; RA Yi C., Chen B., Qi B., Zhang W., Jia G., Zhang L., Li C.J., Dinner A.R., RA Yang C.G., He C.; RT "Duplex interrogation by a direct DNA repair protein in search of base RT damage."; RL Nat. Struct. Mol. Biol. 19:671-676(2012). CC -!- FUNCTION: Dioxygenase that repairs alkylated nucleic acid bases by CC direct reversal oxidative dealkylation. Can process both double- CC stranded (ds) and single-stranded (ss) DNA substrates, with a strong CC preference for dsDNA (PubMed:12486230, PubMed:12594517, CC PubMed:16174769, PubMed:20714506, PubMed:25797601, PubMed:23972994). CC Uses molecular oxygen, 2-oxoglutarate and iron as cofactors to oxidize CC the alkyl groups that are subsequently released as aldehydes, CC regenerating the undamaged bases. Probes the base pair stability, CC locates a weakened base pair and flips the damaged base to accommodate CC the lesion in its active site for efficient catalysis (PubMed:18432238, CC PubMed:22659876). Repairs monoalkylated bases, specifically N1- CC methyladenine and N3-methylcytosine, as well as higher order alkyl CC adducts such as bases modified with exocyclic bridged adducts known as CC etheno adducts including 1,N6-ethenoadenine, 3,N4-ethenocytosine and CC 1,N2-ethenoguanine (PubMed:12486230, PubMed:12594517, PubMed:16174769, CC PubMed:20714506, PubMed:25797601, PubMed:23972994, PubMed:26408825). CC Acts as a gatekeeper of genomic integrity under alkylation stress. CC Efficiently repairs alkylated lesions in ribosomal DNA (rDNA). These CC lesions can cause ss- and dsDNA strand breaks that severely impair rDNA CC transcription (PubMed:23972994). In a response mechanism to DNA damage, CC associates with PCNA at replication forks to repair alkylated adducts CC prior to replication (PubMed:19736315, PubMed:26408825). CC {ECO:0000269|PubMed:12486230, ECO:0000269|PubMed:12594517, CC ECO:0000269|PubMed:16174769, ECO:0000269|PubMed:18432238, CC ECO:0000269|PubMed:19736315, ECO:0000269|PubMed:20714506, CC ECO:0000269|PubMed:22659876, ECO:0000269|PubMed:23972994, CC ECO:0000269|PubMed:25797601, ECO:0000269|PubMed:26408825}. CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + a methylated nucleobase within DNA + O2 = a CC nucleobase within DNA + CO2 + formaldehyde + succinate; CC Xref=Rhea:RHEA:30299, Rhea:RHEA-COMP:12192, Rhea:RHEA-COMP:12193, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:32875, CC ChEBI:CHEBI:64428; EC=1.14.11.33; CC Evidence={ECO:0000269|PubMed:12486230, ECO:0000269|PubMed:16174769, CC ECO:0000269|PubMed:18432238, ECO:0000269|PubMed:20714506, CC ECO:0000269|PubMed:22659876}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:30300; CC Evidence={ECO:0000305|PubMed:12486230, ECO:0000305|PubMed:16174769, CC ECO:0000305|PubMed:18432238, ECO:0000305|PubMed:20714506, CC ECO:0000305|PubMed:22659876}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + an N(1)-methyl-2'-deoxyadenosine in double- CC stranded DNA + O2 = a 2'-deoxyadenosine in double-stranded DNA + CO2 CC + formaldehyde + H(+) + succinate; Xref=Rhea:RHEA:70443, Rhea:RHEA- CC COMP:14236, Rhea:RHEA-COMP:17897, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:90615, CC ChEBI:CHEBI:139096; Evidence={ECO:0000269|PubMed:16174769, CC ECO:0000269|PubMed:18432238, ECO:0000269|PubMed:20714506, CC ECO:0000269|PubMed:22659876}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70444; CC Evidence={ECO:0000305|PubMed:16174769, ECO:0000305|PubMed:18432238, CC ECO:0000305|PubMed:20714506, ECO:0000305|PubMed:22659876}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + an N(1)-methyl-2'-deoxyadenosine in single- CC stranded DNA + O2 = a 2'-deoxyadenosine in single-stranded DNA + CO2 CC + formaldehyde + H(+) + succinate; Xref=Rhea:RHEA:70447, Rhea:RHEA- CC COMP:17895, Rhea:RHEA-COMP:17896, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:90615, CC ChEBI:CHEBI:139096; Evidence={ECO:0000269|PubMed:12486230, CC ECO:0000269|PubMed:16174769, ECO:0000269|PubMed:20714506, CC ECO:0000269|PubMed:22659876}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70448; CC Evidence={ECO:0000305|PubMed:12486230, ECO:0000305|PubMed:16174769, CC ECO:0000305|PubMed:20714506, ECO:0000305|PubMed:22659876}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + an N(3)-methyl-2'-deoxycytidine in double- CC stranded DNA + O2 = a 2'-deoxycytidine in double-stranded DNA + CO2 + CC formaldehyde + H(+) + succinate; Xref=Rhea:RHEA:70439, Rhea:RHEA- CC COMP:14237, Rhea:RHEA-COMP:17070, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:85452, CC ChEBI:CHEBI:139075; Evidence={ECO:0000269|PubMed:16174769}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70440; CC Evidence={ECO:0000305|PubMed:16174769}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + an N(3)-methyl-2'-deoxycytidine in single- CC stranded DNA + O2 = a 2'-deoxycytidine in single-stranded DNA + CO2 + CC formaldehyde + H(+) + succinate; Xref=Rhea:RHEA:70435, Rhea:RHEA- CC COMP:12846, Rhea:RHEA-COMP:17894, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:85452, CC ChEBI:CHEBI:139075; Evidence={ECO:0000269|PubMed:12486230, CC ECO:0000269|PubMed:16174769}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70436; CC Evidence={ECO:0000305|PubMed:12486230, ECO:0000305|PubMed:16174769}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + a 1,N(6)-etheno-2'-deoxyadenosine in double- CC stranded DNA + H2O + O2 = a 2'-deoxyadenosine in double-stranded DNA CC + CO2 + glyoxal + succinate; Xref=Rhea:RHEA:70463, Rhea:RHEA- CC COMP:17897, Rhea:RHEA-COMP:17903, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:30031, ChEBI:CHEBI:34779, ChEBI:CHEBI:90615, CC ChEBI:CHEBI:189583; Evidence={ECO:0000269|PubMed:25797601}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70464; CC Evidence={ECO:0000305|PubMed:25797601}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + a 1,N(6)-etheno-2'-deoxyadenosine in single- CC stranded DNA + H2O + O2 = a 2'-deoxyadenosine in single-stranded DNA CC + CO2 + glyoxal + succinate; Xref=Rhea:RHEA:70459, Rhea:RHEA- CC COMP:17896, Rhea:RHEA-COMP:17904, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:30031, ChEBI:CHEBI:34779, ChEBI:CHEBI:90615, CC ChEBI:CHEBI:189583; Evidence={ECO:0000269|PubMed:25797601}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70460; CC Evidence={ECO:0000305|PubMed:25797601}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + a 3,N(4)-etheno-2'-deoxycytidine in double- CC stranded DNA + H2O + O2 = a 2'-deoxycytidine in double-stranded DNA + CC CO2 + glyoxal + succinate; Xref=Rhea:RHEA:70467, Rhea:RHEA- CC COMP:17070, Rhea:RHEA-COMP:17905, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:30031, ChEBI:CHEBI:34779, ChEBI:CHEBI:85452, CC ChEBI:CHEBI:189585; Evidence={ECO:0000269|PubMed:25797601}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70468; CC Evidence={ECO:0000305|PubMed:25797601}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + a 3,N(4)-etheno-2'-deoxycytidine in single- CC stranded DNA + H2O + O2 = a 2'-deoxycytidine in single-stranded DNA + CC CO2 + glyoxal + succinate; Xref=Rhea:RHEA:70471, Rhea:RHEA- CC COMP:12846, Rhea:RHEA-COMP:17906, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:30031, ChEBI:CHEBI:34779, ChEBI:CHEBI:85452, CC ChEBI:CHEBI:189585; Evidence={ECO:0000269|PubMed:25797601}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70472; CC Evidence={ECO:0000305|PubMed:25797601}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2-oxoglutarate + a 1,N(2)-etheno-2'-deoxyguanosine in double- CC stranded DNA + H2O + O2 = a 2'-deoxyguanosine in double-stranded DNA CC + CO2 + glyoxal + succinate; Xref=Rhea:RHEA:70487, Rhea:RHEA- CC COMP:17910, Rhea:RHEA-COMP:17912, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, CC ChEBI:CHEBI:30031, ChEBI:CHEBI:34779, ChEBI:CHEBI:85445, CC ChEBI:CHEBI:189586; Evidence={ECO:0000269|PubMed:25797601}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70488; CC Evidence={ECO:0000305|PubMed:25797601}; CC -!- COFACTOR: CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000255|PROSITE- CC ProRule:PRU00805, ECO:0000269|PubMed:18432238, CC ECO:0000269|PubMed:18519673}; CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000255|PROSITE- CC ProRule:PRU00805, ECO:0000269|PubMed:18432238, CC ECO:0000269|PubMed:18519673}; CC -!- ACTIVITY REGULATION: Activated by ascorbate and magnesium ions. CC {ECO:0000269|PubMed:12486230, ECO:0000269|PubMed:18519673}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=183 nM for N(1)-methyl-2'-deoxyadenosine in single-stranded DNA CC {ECO:0000269|PubMed:16174769}; CC KM=320 nM for N(1)-methyl-2'-deoxyadenosine in double-stranded DNA CC {ECO:0000269|PubMed:16174769}; CC KM=82.2 nM for N(3)-methyl-2'-deoxycytidine in single-stranded DNA CC {ECO:0000269|PubMed:16174769}; CC KM=167 nM for N(3)-methyl-2'-deoxycytidine in double-stranded DNA CC {ECO:0000269|PubMed:16174769}; CC -!- SUBUNIT: Interacts with PCNA homotrimer; this interaction is enhanced CC during the S-phase of the cell cycle (PubMed:19736315, PubMed:26408825, CC PubMed:23972994). Interacts with nucleolar proteins NCL, UBTF and NPM1 CC (PubMed:23972994). Interacts with XRCC5-XRCC6 heterodimer CC (PubMed:23972994). {ECO:0000269|PubMed:19736315, CC ECO:0000269|PubMed:23972994, ECO:0000269|PubMed:26408825}. CC -!- INTERACTION: CC Q6NS38; Q08379: GOLGA2; NbExp=3; IntAct=EBI-2371780, EBI-618309; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12486230, CC ECO:0000269|PubMed:12594517, ECO:0000269|PubMed:19736315}. Nucleus, CC nucleolus {ECO:0000269|PubMed:23972994}. Nucleus, nucleoplasm CC {ECO:0000269|PubMed:23972994}. Note=Relocates to the replication foci CC during S-phase. {ECO:0000269|PubMed:12594517}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q6NS38-1; Sequence=Displayed; CC Name=2; CC IsoId=Q6NS38-2; Sequence=VSP_042923; CC -!- TISSUE SPECIFICITY: Detected in colon, small intestine, ovary, testis, CC prostate, skeletal muscle, heart, liver and urinary bladder. CC {ECO:0000269|PubMed:12486230, ECO:0000269|PubMed:16174769}. CC -!- DOMAIN: The PCNA-binding motif (AlkB homolog 2 PCNA-interacting motif, CC APIM), mediates the colocalization of ALKBH2 with PCNA at the CC replication foci, coordinating the repair of alkylated DNA damage with CC DNA replication. {ECO:0000269|PubMed:19736315}. CC -!- SIMILARITY: Belongs to the alkB family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY754389; AAV28301.1; -; mRNA. DR EMBL; AB277859; BAF56576.1; -; mRNA. DR EMBL; AC011596; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC070489; AAH70489.1; -; mRNA. DR CCDS; CCDS31897.1; -. [Q6NS38-1] DR CCDS; CCDS55883.1; -. [Q6NS38-2] DR RefSeq; NP_001001655.1; NM_001001655.2. [Q6NS38-1] DR RefSeq; NP_001138846.1; NM_001145374.1. [Q6NS38-1] DR RefSeq; NP_001138847.1; NM_001145375.1. [Q6NS38-1] DR RefSeq; NP_001192108.1; NM_001205179.1. [Q6NS38-2] DR RefSeq; NP_001192109.1; NM_001205180.1. [Q6NS38-2] DR RefSeq; XP_005253892.1; XM_005253835.4. [Q6NS38-1] DR RefSeq; XP_005253893.1; XM_005253836.1. [Q6NS38-2] DR PDB; 3BTX; X-ray; 2.00 A; A=56-258. DR PDB; 3BTY; X-ray; 2.35 A; A=56-258. DR PDB; 3BTZ; X-ray; 3.00 A; A=57-258. DR PDB; 3BU0; X-ray; 2.50 A; A=56-258. DR PDB; 3BUC; X-ray; 2.59 A; A=56-258. DR PDB; 3H8O; X-ray; 2.50 A; A=56-261. DR PDB; 3H8R; X-ray; 1.77 A; A=56-261. DR PDB; 3H8X; X-ray; 2.50 A; A=56-261. DR PDB; 3RZG; X-ray; 1.62 A; A=56-261. DR PDB; 3RZH; X-ray; 2.25 A; A=56-261. DR PDB; 3RZJ; X-ray; 2.50 A; A=56-261. DR PDB; 3RZK; X-ray; 2.78 A; A=56-261. DR PDB; 3RZL; X-ray; 2.60 A; A/D=56-261. DR PDB; 3RZM; X-ray; 3.06 A; A=56-260. DR PDB; 3S57; X-ray; 1.60 A; A=56-258. DR PDB; 3S5A; X-ray; 1.70 A; A=56-258. DR PDB; 4MG2; X-ray; 2.30 A; A=56-258. DR PDB; 4MGT; X-ray; 2.60 A; A=56-258. DR PDBsum; 3BTX; -. DR PDBsum; 3BTY; -. DR PDBsum; 3BTZ; -. DR PDBsum; 3BU0; -. DR PDBsum; 3BUC; -. DR PDBsum; 3H8O; -. DR PDBsum; 3H8R; -. DR PDBsum; 3H8X; -. DR PDBsum; 3RZG; -. DR PDBsum; 3RZH; -. DR PDBsum; 3RZJ; -. DR PDBsum; 3RZK; -. DR PDBsum; 3RZL; -. DR PDBsum; 3RZM; -. DR PDBsum; 3S57; -. DR PDBsum; 3S5A; -. DR PDBsum; 4MG2; -. DR PDBsum; 4MGT; -. DR AlphaFoldDB; Q6NS38; -. DR SMR; Q6NS38; -. DR BioGRID; 125741; 19. DR IntAct; Q6NS38; 11. DR STRING; 9606.ENSP00000398181; -. DR BindingDB; Q6NS38; -. DR ChEMBL; CHEMBL5169164; -. DR DrugBank; DB00126; Ascorbic acid. DR iPTMnet; Q6NS38; -. DR PhosphoSitePlus; Q6NS38; -. DR SwissPalm; Q6NS38; -. DR BioMuta; ALKBH2; -. DR DMDM; 74736661; -. DR EPD; Q6NS38; -. DR jPOST; Q6NS38; -. DR MassIVE; Q6NS38; -. DR MaxQB; Q6NS38; -. DR PaxDb; 9606-ENSP00000398181; -. DR PeptideAtlas; Q6NS38; -. DR ProteomicsDB; 66621; -. [Q6NS38-1] DR ProteomicsDB; 66622; -. [Q6NS38-2] DR Pumba; Q6NS38; -. DR Antibodypedia; 4403; 159 antibodies from 30 providers. DR DNASU; 121642; -. DR Ensembl; ENST00000343075.7; ENSP00000343021.3; ENSG00000189046.11. [Q6NS38-1] DR Ensembl; ENST00000429722.3; ENSP00000398181.1; ENSG00000189046.11. [Q6NS38-1] DR Ensembl; ENST00000440112.2; ENSP00000399820.2; ENSG00000189046.11. [Q6NS38-2] DR Ensembl; ENST00000619381.4; ENSP00000478765.1; ENSG00000189046.11. [Q6NS38-2] DR GeneID; 121642; -. DR KEGG; hsa:121642; -. DR MANE-Select; ENST00000429722.3; ENSP00000398181.1; NM_001145374.2; NP_001138846.1. DR UCSC; uc001tnx.3; human. [Q6NS38-1] DR AGR; HGNC:32487; -. DR CTD; 121642; -. DR DisGeNET; 121642; -. DR GeneCards; ALKBH2; -. DR HGNC; HGNC:32487; ALKBH2. DR HPA; ENSG00000189046; Low tissue specificity. DR MIM; 610602; gene. DR neXtProt; NX_Q6NS38; -. DR OpenTargets; ENSG00000189046; -. DR PharmGKB; PA143485292; -. DR VEuPathDB; HostDB:ENSG00000189046; -. DR eggNOG; ENOG502QTDK; Eukaryota. DR GeneTree; ENSGT00940000159009; -. DR HOGENOM; CLU_048788_5_0_1; -. DR InParanoid; Q6NS38; -. DR OMA; TQHHWQH; -. DR OrthoDB; 5483680at2759; -. DR PhylomeDB; Q6NS38; -. DR TreeFam; TF331732; -. DR BRENDA; 1.14.11.33; 2681. DR PathwayCommons; Q6NS38; -. DR Reactome; R-HSA-112122; ALKBH2 mediated reversal of alkylation damage. DR SignaLink; Q6NS38; -. DR BioGRID-ORCS; 121642; 7 hits in 1158 CRISPR screens. DR ChiTaRS; ALKBH2; human. DR EvolutionaryTrace; Q6NS38; -. DR GenomeRNAi; 121642; -. DR Pharos; Q6NS38; Tbio. DR PRO; PR:Q6NS38; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q6NS38; Protein. DR Bgee; ENSG00000189046; Expressed in oocyte and 148 other cell types or tissues. DR ExpressionAtlas; Q6NS38; baseline and differential. DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0051747; F:cytosine C-5 DNA demethylase activity; IDA:UniProtKB. DR GO; GO:0043734; F:DNA-N1-methyladenine dioxygenase activity; IDA:UniProtKB. DR GO; GO:0008198; F:ferrous iron binding; IDA:UniProtKB. DR GO; GO:0035516; F:oxidative DNA demethylase activity; IDA:UniProtKB. DR GO; GO:0000182; F:rDNA binding; IDA:UniProtKB. DR GO; GO:0006307; P:DNA dealkylation involved in DNA repair; IDA:UniProtKB. DR GO; GO:0080111; P:DNA demethylation; TAS:BHF-UCL. DR GO; GO:0070989; P:oxidative demethylation; TAS:BHF-UCL. DR Gene3D; 2.60.120.590; Alpha-ketoglutarate-dependent dioxygenase AlkB-like; 1. DR InterPro; IPR027450; AlkB-like. DR InterPro; IPR037151; AlkB-like_sf. DR InterPro; IPR032852; ALKBH2. DR InterPro; IPR005123; Oxoglu/Fe-dep_dioxygenase. DR PANTHER; PTHR31573; ALPHA-KETOGLUTARATE-DEPENDENT DIOXYGENASE ALKB HOMOLOG 2; 1. DR PANTHER; PTHR31573:SF1; DNA OXIDATIVE DEMETHYLASE ALKBH2; 1. DR Pfam; PF13532; 2OG-FeII_Oxy_2; 1. DR SUPFAM; SSF51197; Clavaminate synthase-like; 1. DR PROSITE; PS51471; FE2OG_OXY; 1. DR Genevisible; Q6NS38; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Dioxygenase; DNA damage; DNA repair; KW Iron; Magnesium; Metal-binding; Nucleus; Oxidoreductase; KW Reference proteome. FT CHAIN 1..261 FT /note="DNA oxidative demethylase ALKBH2" FT /id="PRO_0000239275" FT DOMAIN 152..257 FT /note="Fe2OG dioxygenase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805" FT REGION 1..57 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 3..7 FT /note="PCNA-binding" FT /evidence="ECO:0000269|PubMed:19736315" FT COMPBIAS 31..46 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 102..104 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:18432238" FT BINDING 122..124 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:18432238" FT BINDING 159 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000269|PubMed:18432238, FT ECO:0000269|PubMed:22659876" FT BINDING 161 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000269|PubMed:18432238, FT ECO:0000269|PubMed:22659876" FT BINDING 171 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000269|PubMed:18432238" FT BINDING 171 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:18432238" FT BINDING 173 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:18432238" FT BINDING 174 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:18432238" FT BINDING 236 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000269|PubMed:18432238" FT BINDING 236 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:18432238" FT BINDING 248 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000269|PubMed:18432238, FT ECO:0000269|PubMed:22659876" FT BINDING 252 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000269|PubMed:22659876" FT BINDING 254 FT /ligand="2-oxoglutarate" FT /ligand_id="ChEBI:CHEBI:16810" FT /evidence="ECO:0000269|PubMed:18432238, FT ECO:0000269|PubMed:22659876" FT VAR_SEQ 95..261 FT /note="ALARVQVFGKWHSVPRKQATYGDAGLTYTFSGLTLSPKPWIPVLERIRDHVS FT GVTGQTFNFVLINRYKDGCDHIGEHRDDERELAPGSPIASVSFGACRDFVFRHKDSRGK FT SPSRRVAVVRLPLAHGSLLMMNHPTNTHWYHSLPVRKKVLAPRVNLTFRKILLTKK -> FT IKMAVTTSGSTEMMKENWPLGAPLPLSPSVPAETLSSGIRIPVGKAPPGGWRWSGCRWP FT TGAY (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17979886" FT /id="VSP_042923" FT VARIANT 9 FT /note="A -> V (found in a patient with endometrial cancer; FT slightly decreased PCNA-binding)" FT /evidence="ECO:0000269|PubMed:26408825" FT /id="VAR_086049" FT VARIANT 10 FT /note="Q -> K (increased PCNA-binding; dbSNP:rs138073204)" FT /evidence="ECO:0000269|PubMed:26408825" FT /id="VAR_086050" FT VARIANT 203 FT /note="R -> H (in dbSNP:rs33962311)" FT /id="VAR_048223" FT MUTAGEN 3 FT /note="R->K: Impairs PCNA-binding. No effect on FT PCNA-binding; when associated with R-7." FT /evidence="ECO:0000269|PubMed:19736315" FT MUTAGEN 4 FT /note="F->A: Complete loss of PCNA-binding." FT /evidence="ECO:0000269|PubMed:19736315, FT ECO:0000269|PubMed:26408825" FT MUTAGEN 4 FT /note="F->Y: No effect on PCNA-binding." FT /evidence="ECO:0000269|PubMed:19736315" FT MUTAGEN 5..6 FT /note="LV->AA: Strong decrease in PCNA-binding." FT /evidence="ECO:0000269|PubMed:19736315" FT MUTAGEN 7 FT /note="K->R: No effect on PCNA-binding; when associated FT with K-3." FT /evidence="ECO:0000269|PubMed:19736315" FT MUTAGEN 38..40 FT /note="RKR->AAA: Leads to cytoplasmic relocalization." FT /evidence="ECO:0000269|PubMed:23972994" FT MUTAGEN 101..103 FT /note="VFG->RED: Strong decrease of activity toward FT N1-methyladenine adduct in both ssDNA and dsDNA FT substrates." FT /evidence="ECO:0000269|PubMed:20714506" FT MUTAGEN 101 FT /note="V->A: Decreases activity toward N1-methyladenine FT adduct in ssDNA. Has no effect on lesion repair in dsDNA." FT /evidence="ECO:0000269|PubMed:20714506" FT MUTAGEN 101 FT /note="V->G: Loss of activity toward N1-methyladenine FT adduct in either ssDNA or dsDNA; when associated with FT A-102." FT /evidence="ECO:0000269|PubMed:22659876" FT MUTAGEN 102 FT /note="F->A: Strong decrease of activity toward FT N1-methyladenine adduct. Loss of activity toward FT N1-methyladenine adduct in either ssDNA or dsDNA; when FT associated with G-101." FT /evidence="ECO:0000269|PubMed:20714506, FT ECO:0000269|PubMed:22659876" FT MUTAGEN 110 FT /note="R->A: Loss of activity toward N1-methyladenine FT adduct in either ssDNA or dsDNA." FT /evidence="ECO:0000269|PubMed:20714506" FT MUTAGEN 122 FT /note="Y->A: Decreases activity toward N1-methyladenine FT adduct in either ssDNA or dsDNA." FT /evidence="ECO:0000269|PubMed:20714506" FT MUTAGEN 124 FT /note="F->A: Loss of activity toward N1-methyladenine FT adduct in either ssDNA or dsDNA." FT /evidence="ECO:0000269|PubMed:20714506" FT MUTAGEN 125 FT /note="S->A: Strong decrease of activity toward FT N1-methyladenine adduct in ssDNA. Has no effect on lesion FT repair in dsDNA." FT /evidence="ECO:0000269|PubMed:20714506" FT MUTAGEN 173 FT /note="D->A: Loss of activity associated with decreased FT rDNA transcription." FT /evidence="ECO:0000269|PubMed:16174769, FT ECO:0000269|PubMed:23972994" FT MUTAGEN 175 FT /note="E->A: Loss of activity." FT /evidence="ECO:0000269|PubMed:20714506" FT MUTAGEN 236 FT /note="H->A: Decreases activity." FT /evidence="ECO:0000269|PubMed:16174769" FT CONFLICT 43 FT /note="R -> G (in Ref. 1; AAV28301)" FT /evidence="ECO:0000305" FT STRAND 58..62 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 65..71 FT /evidence="ECO:0007829|PDB:3S57" FT HELIX 75..88 FT /evidence="ECO:0007829|PDB:3S57" FT HELIX 94..97 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 98..101 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 104..107 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 109..116 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 122..124 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 127..129 FT /evidence="ECO:0007829|PDB:3S57" FT HELIX 136..149 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 154..163 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 168..171 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 176..178 FT /evidence="ECO:0007829|PDB:3RZG" FT STRAND 184..191 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 193..199 FT /evidence="ECO:0007829|PDB:3S57" FT HELIX 200..202 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 204..206 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 214..218 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 222..227 FT /evidence="ECO:0007829|PDB:3S57" FT HELIX 230..233 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 234..238 FT /evidence="ECO:0007829|PDB:3S57" FT STRAND 248..254 FT /evidence="ECO:0007829|PDB:3S57" SQ SEQUENCE 261 AA; 29322 MW; A376E13F92621A01 CRC64; MDRFLVKGAQ GGLLRKQEEQ EPTGEEPAVL GGDKESTRKR PRREAPGNGG HSAGPSWRHI RAEGLDCSYT VLFGKAEADE IFQELEKEVE YFTGALARVQ VFGKWHSVPR KQATYGDAGL TYTFSGLTLS PKPWIPVLER IRDHVSGVTG QTFNFVLINR YKDGCDHIGE HRDDERELAP GSPIASVSFG ACRDFVFRHK DSRGKSPSRR VAVVRLPLAH GSLLMMNHPT NTHWYHSLPV RKKVLAPRVN LTFRKILLTK K //