ALKB2_HUMAN
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 03-AUG-2022, entry version 147.
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;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00805,
CC ECO:0000269|PubMed:18432238, 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}.
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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; 16.
DR IntAct; Q6NS38; 11.
DR STRING; 9606.ENSP00000398181; -.
DR DrugBank; DB00126; Ascorbic acid.
DR iPTMnet; Q6NS38; -.
DR PhosphoSitePlus; Q6NS38; -.
DR BioMuta; ALKBH2; -.
DR DMDM; 74736661; -.
DR EPD; Q6NS38; -.
DR jPOST; Q6NS38; -.
DR MassIVE; Q6NS38; -.
DR MaxQB; Q6NS38; -.
DR PaxDb; Q6NS38; -.
DR PeptideAtlas; Q6NS38; -.
DR PRIDE; Q6NS38; -.
DR ProteomicsDB; 66621; -. [Q6NS38-1]
DR ProteomicsDB; 66622; -. [Q6NS38-2]
DR Antibodypedia; 4403; 145 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 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; 1379174at2759; -.
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 1080 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 146 other tissues.
DR ExpressionAtlas; Q6NS38; baseline and differential.
DR Genevisible; Q6NS38; HS.
DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:UniProtKB.
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 GO; GO:0035511; P:oxidative DNA demethylation; IDA:UniProtKB.
DR Gene3D; 2.60.120.590; -; 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; PTHR31573; 1.
DR Pfam; PF13532; 2OG-FeII_Oxy_2; 1.
DR PROSITE; PS51471; FE2OG_OXY; 1.
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 PCNA-
FT 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 N1-
FT methyladenine adduct in both ssDNA and dsDNA 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 A-
FT 102."
FT /evidence="ECO:0000269|PubMed:22659876"
FT MUTAGEN 102
FT /note="F->A: Strong decrease of activity toward N1-
FT methyladenine adduct. Loss of activity toward N1-
FT 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 N1-
FT 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
