RBCC Red Blood Cell Collection

APEX1 (APE, APE1, APEX, APX, HAP1, REF1) [Confidence: low (only semi-automatic identification from reviews)]
DNA-(apurinic or apyrimidinic site) lyase; 3.1.-.-; 4.2.99.18 (APEX nuclease; APEN; Apurinic-apyrimidinic endonuclease 1; AP endonuclease 1; APE-1; REF-1; Redox factor-1; DNA-(apurinic or apyrimidinic site) lyase, mitochondrial)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P27695
ID APEX1_HUMAN Reviewed; 318 AA.
AC P27695; Q969L5; Q99775;
DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 177.
DE RecName: Full=DNA-(apurinic or apyrimidinic site) lyase;
DE EC=3.1.-.-;
DE EC=4.2.99.18;
DE AltName: Full=APEX nuclease;
DE Short=APEN;
DE AltName: Full=Apurinic-apyrimidinic endonuclease 1;
DE Short=AP endonuclease 1;
DE Short=APE-1;
DE AltName: Full=REF-1;
DE AltName: Full=Redox factor-1;
DE Contains:
DE RecName: Full=DNA-(apurinic or apyrimidinic site) lyase, mitochondrial;
GN Name=APEX1; Synonyms=APE, APE1, APEX, APX, HAP1, REF1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RC TISSUE=Melanocyte;
RX PubMed=1719477; DOI=10.1093/nar/19.20.5519;
RA Robson C.N., Hickson I.D.;
RT "Isolation of cDNA clones encoding a human apurinic/apyrimidinic
RT endonuclease that corrects DNA repair and mutagenesis defects in E.
RT coli xth (exonuclease III) mutants.";
RL Nucleic Acids Res. 19:5519-5523(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=1722334; DOI=10.1073/pnas.88.24.11450;
RA Demple B., Herman T., Chen D.S.;
RT "Cloning and expression of APE, the cDNA encoding the major human
RT apurinic endonuclease: definition of a family of DNA repair enzymes.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:11450-11454(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC TISSUE=Bone marrow, and Leukocyte;
RX PubMed=1627644; DOI=10.1016/0167-4781(92)90027-W;
RA Seki S., Hatsushika M., Watanabe S., Akiyama K., Nagao K., Tsutsui K.;
RT "cDNA cloning, sequencing, expression and possible domain structure of
RT human APEX nuclease homologous to Escherichia coli exonuclease III.";
RL Biochim. Biophys. Acta 1131:287-299(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 2-21.
RX PubMed=1380454;
RA Xanthoudakis S., Miao G., Wang F., Pan Y.-C.E., Curran T.;
RT "Redox activation of Fos-Jun DNA binding activity is mediated by a DNA
RT repair enzyme.";
RL EMBO J. 11:3323-3335(1992).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Carcinoma;
RX PubMed=1371347; DOI=10.1093/nar/20.2.370;
RA Cheng X.B., Bunville J., Patterson T.A.;
RT "Nucleotide sequence of a cDNA for an apurinic/apyrimidinic
RT endonuclease from HeLa cells.";
RL Nucleic Acids Res. 20:370-370(1992).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Leukocyte;
RX PubMed=1380694; DOI=10.1093/nar/20.15.4097;
RA Zhao B., Grandy D.K., Hagerup J.M., Magenis R.E., Smith L.,
RA Chauhan B.C., Henner W.D.;
RT "The human gene for apurinic/apyrimidinic endonuclease (HAP1):
RT sequence and localization to chromosome 14 band q12.";
RL Nucleic Acids Res. 20:4097-4098(1992).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1383925; DOI=10.1093/nar/20.17.4417;
RA Robson C.N., Hocchauser D., Craig R., Rack K., Buckle I.D.,
RA Hickson I.D.;
RT "Structure of the human DNA repair gene HAP1 and its localisation to
RT chromosome 14q 11.2-12.";
RL Nucleic Acids Res. 20:4417-4421(1992).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8086453; DOI=10.1016/0167-4781(94)90241-0;
RA Akiyama K., Seki S., Oshida T., Yoshida M.;
RT "Structure, promoter analysis and chromosomal assignment of the human
RT APEX gene.";
RL Biochim. Biophys. Acta 1219:15-25(1994).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=9110174;
RA Yu W., Andersson B., Worley K.C., Muzny D.M., Ding Y., Liu W.,
RA Ricafrente J.Y., Wentland M.A., Lennon G., Gibbs R.A.;
RT "Large-scale concatenation cDNA sequencing.";
RL Genome Res. 7:353-358(1997).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS HIS-51; VAL-64 AND
RP GLU-148.
RG NIEHS SNPs program;
RL Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLU-148.
RC TISSUE=Brain, Lung, and 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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [14]
RP PROTEIN SEQUENCE OF 2-10, FUNCTION, INTERACTION WITH GZMA, CLEAVAGE BY
RP GRANZYME A, IDENTIFICATION IN THE SET COMPLEX, MUTAGENESIS OF LYS-31;
RP CYS-65 AND ASP-210, AND SUBCELLULAR LOCATION.
RX PubMed=12524539; DOI=10.1038/ni885;
RA Fan Z., Beresford P.J., Zhang D., Xu Z., Novina C.D., Yoshida A.,
RA Pommier Y., Lieberman J.;
RT "Cleaving the oxidative repair protein Ape1 enhances cell death
RT mediated by granzyme A.";
RL Nat. Immunol. 4:145-153(2003).
RN [15]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-146.
RC TISSUE=Placenta;
RX PubMed=1284593; DOI=10.1093/hmg/1.9.677;
RA Harrison L., Ascione G., Menninger J.C., Ward D.C., Demple B.;
RT "Human apurinic endonuclease gene (APE): structure and genomic mapping
RT (chromosome 14q11.2-12).";
RL Hum. Mol. Genet. 1:677-680(1992).
RN [16]
RP FUNCTION, AND MUTAGENESIS OF CYS-65; CYS-93; CYS-99; CYS-138; CYS-208;
RP CYS-296 AND CYS-310.
RX PubMed=8355688;
RA Walker L.J., Robson C.N., Black E., Gillespie D., Hickson I.D.;
RT "Identification of residues in the human DNA repair enzyme HAP1 (Ref-
RT 1) that are essential for redox regulation of Jun DNA binding.";
RL Mol. Cell. Biol. 13:5370-5376(1993).
RN [17]
RP FUNCTION, AND INTERACTION WITH XRCC5 AND XRCC6.
RX PubMed=8621488; DOI=10.1074/jbc.271.15.8593;
RA Chung U., Igarashi T., Nishishita T., Iwanari H., Iwamatsu A.,
RA Suwa A., Mimori T., Hata K., Ebisu S., Ogata E., Fujita T.,
RA Okazaki T.;
RT "The interaction between Ku antigen and REF1 protein mediates negative
RT gene regulation by extracellular calcium.";
RL J. Biol. Chem. 271:8593-8598(1996).
RN [18]
RP FUNCTION, AND MUTAGENESIS OF ASN-212.
RX PubMed=8932375; DOI=10.1093/nar/24.21.4217;
RA Rothwell D.G., Hickson I.D.;
RT "Asparagine 212 is essential for abasic site recognition by the human
RT DNA repair endonuclease HAP1.";
RL Nucleic Acids Res. 24:4217-4221(1996).
RN [19]
RP FUNCTION, SUBUNIT, INTERACTION WITH TXN, AND SUBCELLULAR LOCATION.
RX PubMed=9108029; DOI=10.1073/pnas.94.8.3633;
RA Hirota K., Matsui M., Iwata S., Nishiyama A., Mori K., Yodoi J.;
RT "AP-1 transcriptional activity is regulated by a direct association
RT between thioredoxin and Ref-1.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:3633-3638(1997).
RN [20]
RP FUNCTION, AND INTERACTION WITH POLB.
RX PubMed=9207062; DOI=10.1073/pnas.94.14.7166;
RA Bennett R.A., Wilson D.M. III, Wong D., Demple B.;
RT "Interaction of human apurinic endonuclease and DNA polymerase beta in
RT the base excision repair pathway.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:7166-7169(1997).
RN [21]
RP CATALYTIC ACTIVITY, FUNCTION, MUTAGENESIS OF ASP-283; ASP-308 AND
RP HIS-309, AND COFACTOR.
RX PubMed=9804799; DOI=10.1074/jbc.273.46.30360;
RA Masuda Y., Bennett R.A., Demple B.;
RT "Rapid dissociation of human apurinic endonuclease (Ape1) from incised
RT DNA induced by magnesium.";
RL J. Biol. Chem. 273:30360-30365(1998).
RN [22]
RP FUNCTION, INDUCTION, AND SUBCELLULAR LOCATION.
RX PubMed=9560228; DOI=10.1073/pnas.95.9.5061;
RA Ramana C.V., Boldogh I., Izumi T., Mitra S.;
RT "Activation of apurinic/apyrimidinic endonuclease in human cells by
RT reactive oxygen species and its correlation with their adaptive
RT response to genotoxicity of free radicals.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:5061-5066(1998).
RN [23]
RP FUNCTION, PHOSPHORYLATION BY CKII, AND SUBCELLULAR LOCATION.
RX PubMed=10023679; DOI=10.1038/sj.onc.1202394;
RA Fritz G., Kaina B.;
RT "Phosphorylation of the DNA repair protein APE/REF-1 by CKII affects
RT redox regulation of AP-1.";
RL Oncogene 18:1033-1040(1999).
RN [24]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=11118054;
RA Wei S.J., Botero A., Hirota K., Bradbury C.M., Markovina S.,
RA Laszlo A., Spitz D.R., Goswami P.C., Yodoi J., Gius D.;
RT "Thioredoxin nuclear translocation and interaction with redox factor-1
RT activates the activator protein-1 transcription factor in response to
RT ionizing radiation.";
RL Cancer Res. 60:6688-6695(2000).
RN [25]
RP FUNCTION, AND PHOSPHORYLATION BY PKC.
RX PubMed=11452037; DOI=10.1093/nar/29.14.3116;
RA Hsieh M.M., Hegde V., Kelley M.R., Deutsch W.A.;
RT "Activation of APE/Ref-1 redox activity is mediated by reactive oxygen
RT species and PKC phosphorylation.";
RL Nucleic Acids Res. 29:3116-3122(2001).
RN [26]
RP FUNCTION.
RX PubMed=11832948; DOI=10.1038/415655a;
RA Chou K.M., Cheng Y.C.;
RT "An exonucleolytic activity of human apurinic/apyrimidinic
RT endonuclease on 3' mispaired DNA.";
RL Nature 415:655-659(2002).
RN [27]
RP FUNCTION, AND INTERACTION WITH HNRNPL.
RX PubMed=11809897; DOI=10.1093/nar/30.3.823;
RA Kuninger D.T., Izumi T., Papaconstantinou J., Mitra S.;
RT "Human AP-endonuclease 1 and hnRNP-L interact with a nCaRE-like
RT repressor element in the AP-endonuclease 1 promoter.";
RL Nucleic Acids Res. 30:823-829(2002).
RN [28]
RP INTERACTION WITH HDAC1; HDAC2 AND HDAC3, ACETYLATION AT LYS-6 AND
RP LYS-7, AND MUTAGENESIS OF LYS-6 AND LYS-7.
RX PubMed=14633989; DOI=10.1093/emboj/cdg595;
RA Bhakat K.K., Izumi T., Yang S.H., Hazra T.K., Mitra S.;
RT "Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation
RT of the parathyroid hormone gene.";
RL EMBO J. 22:6299-6309(2003).
RN [29]
RP CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF TYR-171.
RX PubMed=15380100; DOI=10.1016/j.dnarep.2004.06.009;
RA Mundle S.T., Fattal M.H., Melo L.F., Coriolan J.D., O'Regan N.E.,
RA Strauss P.R.;
RT "Novel role of tyrosine in catalysis by human AP endonuclease 1.";
RL DNA Repair 3:1447-1455(2004).
RN [30]
RP INTERACTION WITH KPNA1 AND KPNA2, MUTAGENESIS OF LYS-6; LYS-7; GLU-12
RP AND ASP-13, AND SUBCELLULAR LOCATION.
RX PubMed=15942031; DOI=10.1093/nar/gki641;
RA Jackson E.B., Theriot C.A., Chattopadhyay R., Mitra S., Izumi T.;
RT "Analysis of nuclear transport signals in the human
RT apurinic/apyrimidinic endonuclease (APE1/Ref1).";
RL Nucleic Acids Res. 33:3303-3312(2005).
RN [31]
RP FUNCTION.
RX PubMed=16617147; DOI=10.1093/nar/gkl177;
RA Chattopadhyay R., Wiederhold L., Szczesny B., Boldogh I., Hazra T.K.,
RA Izumi T., Mitra S.;
RT "Identification and characterization of mitochondrial abasic (AP)-
RT endonuclease in mammalian cells.";
RL Nucleic Acids Res. 34:2067-2076(2006).
RN [32]
RP SUBCELLULAR LOCATION.
RX PubMed=17148573; DOI=10.1242/jcs.03312;
RA Campalans A., Amouroux R., Bravard A., Epe B., Radicella J.P.;
RT "UVA irradiation induces relocalisation of the DNA repair protein
RT hOGG1 to nuclear speckles.";
RL J. Cell Sci. 120:23-32(2007).
RN [33]
RP S-NITROSYLATION AT CYS-65; CYS-93 AND CYS-310 IN RESPONSE TO NITRIC
RP OXIDE, AND SUBCELLULAR LOCATION.
RX PubMed=17403694; DOI=10.1093/nar/gkl1163;
RA Qu J., Liu G.H., Huang B., Chen C.;
RT "Nitric oxide controls nuclear export of APE1/Ref-1 through S-
RT nitrosation of cysteines 93 and 310.";
RL Nucleic Acids Res. 35:2522-2532(2007).
RN [34]
RP FUNCTION.
RX PubMed=18439621; DOI=10.1016/j.jmb.2008.03.053;
RA Berquist B.R., McNeill D.R., Wilson D.M. III;
RT "Characterization of abasic endonuclease activity of human Ape1 on
RT alternative substrates, as well as effects of ATP and sequence context
RT on AP site incision.";
RL J. Mol. Biol. 379:17-27(2008).
RN [35]
RP FUNCTION, INTERACTION WITH MVP AND YBX1, MUTAGENESIS OF LYS-6 AND
RP LYS-7, AND SUBCELLULAR LOCATION.
RX PubMed=18809583; DOI=10.1128/MCB.00244-08;
RA Chattopadhyay R., Das S., Maiti A.K., Boldogh I., Xie J., Hazra T.K.,
RA Kohno K., Mitra S., Bhakat K.K.;
RT "Regulatory role of human AP-endonuclease (APE1/Ref-1) in YB-1-
RT mediated activation of the multidrug resistance gene MDR1.";
RL Mol. Cell. Biol. 28:7066-7080(2008).
RN [36]
RP FUNCTION.
RX PubMed=18179823; DOI=10.1016/j.molimm.2007.11.020;
RA Guo Y., Chen J., Zhao T., Fan Z.;
RT "Granzyme K degrades the redox/DNA repair enzyme Ape1 to trigger
RT oxidative stress of target cells leading to cytotoxicity.";
RL Mol. Immunol. 45:2225-2235(2008).
RN [37]
RP FUNCTION, AND MUTAGENESIS OF CYS-65; CYS-93; CYS-99; CYS-138; CYS-208;
RP CYS-296 AND CYS-310.
RX PubMed=18579163; DOI=10.1016/j.mrfmmm.2008.04.008;
RA Georgiadis M.M., Luo M., Gaur R.K., Delaplane S., Li X., Kelley M.R.;
RT "Evolution of the redox function in mammalian apurinic/apyrimidinic
RT endonuclease.";
RL Mutat. Res. 643:54-63(2008).
RN [38]
RP CATALYTIC ACTIVITY, COFACTOR, AND ENZYME MECHANISM.
RX PubMed=19123919; DOI=10.1021/bi8016137;
RA Mundle S.T., Delaney J.C., Essigmann J.M., Strauss P.R.;
RT "Enzymatic mechanism of human apurinic/apyrimidinic endonuclease
RT against a THF AP site model substrate.";
RL Biochemistry 48:19-26(2009).
RN [39]
RP FUNCTION, INTERACTION WITH KRT8; NPM1; PRDX6; PRPF19; RPLP0 AND WDR77,
RP RNA-BINDING, AND SUBCELLULAR LOCATION.
RX PubMed=19188445; DOI=10.1128/MCB.01337-08;
RA Vascotto C., Fantini D., Romanello M., Cesaratto L., Deganuto M.,
RA Leonardi A., Radicella J.P., Kelley M.R., D'Ambrosio C., Scaloni A.,
RA Quadrifoglio F., Tell G.;
RT "APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in
RT the rRNA quality control process.";
RL Mol. Cell. Biol. 29:1834-1854(2009).
RN [40]
RP FUNCTION, RNA-BINDING, AND MUTAGENESIS OF GLU-96 AND HIS-309.
RX PubMed=19401441; DOI=10.1093/nar/gkp275;
RA Barnes T., Kim W.C., Mantha A.K., Kim S.E., Izumi T., Mitra S.,
RA Lee C.H.;
RT "Identification of apurinic/apyrimidinic endonuclease 1 (APE1) as the
RT endoribonuclease that cleaves c-myc mRNA.";
RL Nucleic Acids Res. 37:3946-3958(2009).
RN [41]
RP INTERACTION WITH MDM2, UBIQUITINATION, AND MUTAGENESIS OF LYS-24;
RP LYS-25 AND LYS-27.
RX PubMed=19219073; DOI=10.1038/onc.2009.5;
RA Busso C.S., Iwakuma T., Izumi T.;
RT "Ubiquitination of mammalian AP endonuclease (APE1) regulated by the
RT p53-MDM2 signaling pathway.";
RL Oncogene 28:1616-1625(2009).
RN [42]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-197, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [43]
RP INTERACTION WITH TOMM20, MUTAGENESIS OF LYS-24; LYS-25; LYS-27;
RP LYS-31; LYS-299; ARG-301 AND LYS-303, AND SUBCELLULAR LOCATION.
RX PubMed=20231292; DOI=10.1074/jbc.M109.069591;
RA Li M., Zhong Z., Zhu J., Xiang D., Dai N., Cao X., Qing Y., Yang Z.,
RA Xie J., Li Z., Baugh L., Wang G., Wang D.;
RT "Identification and characterization of mitochondrial targeting
RT sequence of human apurinic/apyrimidinic endonuclease 1.";
RL J. Biol. Chem. 285:14871-14881(2010).
RN [44]
RP FUNCTION, INTERACTION WITH SIRT1 AND XRCC1, MUTAGENESIS OF LYS-6 AND
RP LYS-7, AND SUBCELLULAR LOCATION.
RX PubMed=19934257; DOI=10.1093/nar/gkp1039;
RA Yamamori T., DeRicco J., Naqvi A., Hoffman T.A., Mattagajasingh I.,
RA Kasuno K., Jung S.B., Kim C.S., Irani K.;
RT "SIRT1 deacetylates APE1 and regulates cellular base excision
RT repair.";
RL Nucleic Acids Res. 38:832-845(2010).
RN [45]
RP FUNCTION, INTERACTION WITH NPM1, RNA-BINDING, ACETYLATION AT LYS-27;
RP LYS-31; LYS-32 AND LYS-35, MUTAGENESIS OF LYS-24; LYS-25; LYS-27;
RP LYS-31 AND LYS-32, AND MASS SPECTROMETRY.
RX PubMed=20699270; DOI=10.1093/nar/gkq691;
RA Fantini D., Vascotto C., Marasco D., D'Ambrosio C., Romanello M.,
RA Vitagliano L., Pedone C., Poletto M., Cesaratto L., Quadrifoglio F.,
RA Scaloni A., Radicella J.P., Tell G.;
RT "Critical lysine residues within the overlooked N-terminal domain of
RT human APE1 regulate its biological functions.";
RL Nucleic Acids Res. 38:8239-8256(2010).
RN [46]
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.,
RA Buerckstuemmer T., 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 [47]
RP FUNCTION IN DNA DEMETHYLATION.
RX PubMed=21496894; DOI=10.1016/j.cell.2011.03.022;
RA Guo J.U., Su Y., Zhong C., Ming G.L., Song H.;
RT "Hydroxylation of 5-methylcytosine by TET1 promotes active DNA
RT demethylation in the adult brain.";
RL Cell 145:423-434(2011).
RN [48]
RP MUTAGENESIS OF ASN-68; ASP-70; TYR-171; PHE-266; ASP-283; ASP-308 AND
RP HIS-309, CATALYTIC ACTIVITY, ACTIVE SITE, FUNCTION, AND COFACTOR.
RX PubMed=21762700; DOI=10.1016/j.jmb.2011.06.050;
RA Kim W.C., Berquist B.R., Chohan M., Uy C., Wilson D.M. III, Lee C.H.;
RT "Characterization of the endoribonuclease active site of human
RT apurinic/apyrimidinic endonuclease 1.";
RL J. Mol. Biol. 411:960-971(2011).
RN [49]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 32-318 IN COMPLEX WITH METAL
RP IONS.
RX PubMed=9351835; DOI=10.1093/emboj/16.21.6548;
RA Gorman M.A., Morera S., Rothwell D.G., de La Fortelle E., Mol C.D.,
RA Tainer J.A., Hickson I.D., Freemont P.S.;
RT "The crystal structure of the human DNA repair endonuclease HAP1
RT suggests the recognition of extra-helical deoxyribose at DNA abasic
RT sites.";
RL EMBO J. 16:6548-6558(1997).
RN [50]
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 40-318 IN COMPLEX WITH DNA
RP AND METAL ION, AND DNA-BINDING.
RX PubMed=10667800; DOI=10.1038/35000249;
RA Mol C.D., Izumi T., Mitra S., Tainer J.A.;
RT "DNA-bound structures and mutants reveal abasic DNA binding by APE1
RT and DNA repair coordination.";
RL Nature 403:451-456(2000).
RN [51]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) IN COMPLEX WITH METAL IONS,
RP CATALYTIC ACTIVITY, AND COFACTOR.
RX PubMed=11286553; DOI=10.1006/jmbi.2001.4529;
RA Beernink P.T., Segelke B.W., Hadi M.Z., Erzberger J.P.,
RA Wilson D.M. III, Rupp B.;
RT "Two divalent metal ions in the active site of a new crystal form of
RT human apurinic/apyrimidinic endonuclease, Ape1: implications for the
RT catalytic mechanism.";
RL J. Mol. Biol. 307:1023-1034(2001).
CC -!- FUNCTION: Multifunctional protein that plays a central role in the
CC cellular response to oxidative stress. The two major activities of
CC APEX1 in DNA repair and redox regulation of transcriptional
CC factors. Functions as a apurinic/apyrimidinic (AP)
CC endodeoxyribonuclease in the DNA base excision repair (BER)
CC pathway of DNA lesions induced by oxidative and alkylating agents.
CC Initiates repair of AP sites in DNA by catalyzing hydrolytic
CC incision of the phosphodiester backbone immediately adjacent to
CC the damage, generating a single-strand break with 5'-deoxyribose
CC phosphate and 3'-hydroxyl ends. Does also incise at AP sites in
CC the DNA strand of DNA/RNA hybrids, single-stranded DNA regions of
CC R-loop structures, and single-stranded RNA molecules. Has a 3'-5'
CC exoribonuclease activity on mismatched deoxyribonucleotides at the
CC 3' termini of nicked or gapped DNA molecules during short-patch
CC BER. Possesses a DNA 3' phosphodiesterase activity capable of
CC removing lesions (such as phosphoglycolate) blocking the 3' side
CC of DNA strand breaks. May also play a role in the epigenetic
CC regulation of gene expression by participating in DNA
CC demethylation. Acts as a loading factor for POLB onto non-incised
CC AP sites in DNA and stimulates the 5'-terminal deoxyribose 5'-
CC phosphate (dRp) excision activity of POLB. Plays a role in the
CC protection from granzymes-mediated cellular repair leading to cell
CC death. Also involved in the DNA cleavage step of class switch
CC recombination (CSR). On the other hand, APEX1 also exerts
CC reversible nuclear redox activity to regulate DNA binding affinity
CC and transcriptional activity of transcriptional factors by
CC controlling the redox status of their DNA-binding domain, such as
CC the FOS/JUN AP-1 complex after exposure to IR. Involved in
CC calcium-dependent down-regulation of parathyroid hormone (PTH)
CC expression by binding to negative calcium response elements
CC (nCaREs). Together with HNRNPL or the dimer XRCC5/XRCC6,
CC associates with nCaRE, acting as an activator of transcriptional
CC repression. Stimulates the YBX1-mediated MDR1 promoter activity,
CC when acetylated at Lys-6 and Lys-7, leading to drug resistance.
CC Acts also as an endoribonuclease involved in the control of
CC single-stranded RNA metabolism. Plays a role in regulating MYC
CC mRNA turnover by preferentially cleaving in between UA and CA
CC dinucleotides of the MYC coding region determinant (CRD). In
CC association with NMD1, plays a role in the rRNA quality control
CC process during cell cycle progression. Associates, together with
CC YBX1, on the MDR1 promoter. Together with NPM1, associates with
CC rRNA. Binds DNA and RNA.
CC -!- CATALYTIC ACTIVITY: The C-O-P bond 3' to the apurinic or
CC apyrimidinic site in DNA is broken by a beta-elimination reaction,
CC leaving a 3'-terminal unsaturated sugar and a product with a
CC terminal 5'-phosphate.
CC -!- COFACTOR: Magnesium. Can also utilize manganese. Probably binds
CC two magnesium or manganese ions per subunit.
CC -!- ENZYME REGULATION: NPM1 stimulates endodeoxyribonuclease activity
CC on double-stranded DNA with AP sites, but inhibits
CC endoribonuclease activity on single-stranded RNA containing AP
CC sites.
CC -!- SUBUNIT: Monomer. Homodimer; disulfide-linked. Component of the
CC SET complex, composed at least of APEX1, GZMA, SET, ANP32A, HMGB2
CC and NME1. Associates with the dimer XRCC5/XRCC6 in a DNA-dependent
CC manner. Interacts with SIRT1; the interaction is increased in the
CC context of genotoxic stress. Interacts with HDAC1, HDAC2 and
CC HDAC3; the interactions are not dependent on the APEX1 acetylation
CC status. Interacts with XRCC1; the interaction is induced by SIRT1
CC and increased with the APEX1 acetylated form. Interacts with NPM1
CC (via N-terminal domain); the interaction is RNA-dependent and
CC decreases in hydrogen peroxide-damaged cells. Interacts (via N-
CC terminus) with YBX1 (via C-terminus); the interaction is increased
CC in presence of APEX1 acetylated at Lys-6 and Lys-7. Interacts with
CC HNRNPL; the interaction is DNA-dependent. Interacts (via N-
CC terminus) with KPNA1 and KPNA2. Interacts with TXN; the
CC interaction stimulates the FOS/JUN AP-1 complex DNA-binding
CC activity in a redox-dependent manner. Interacts with GZMA, KRT8,
CC MDM2, POLB, PRDX6, PRPF19, RPLP0, TOMM20 and WDR77. Binds to CDK5
CC (By similarity).
CC -!- INTERACTION:
CC Q09472:EP300; NbExp=8; IntAct=EBI-1048805, EBI-447295;
CC Q96EB6:SIRT1; NbExp=6; IntAct=EBI-1048805, EBI-1802965;
CC -!- SUBCELLULAR LOCATION: Nucleus. Nucleus, nucleolus. Nucleus
CC speckle. Endoplasmic reticulum. Cytoplasm. Note=Detected in the
CC cytoplasm of B-cells stimulated to switch (By similarity).
CC Colocalized with SIRT1 in the nucleus. Colocalized with YBX1 in
CC nuclear speckles after genotoxic stress. Together with OGG1 is
CC recruited to nuclear speckles in UVA-irradiated cells. Colocalized
CC with nucleolin and NPM1 in the nucleolus. Its nucleolar
CC localization is cell cycle dependent and requires active rRNA
CC transcription. Colocalized with calreticulin in the endoplasmic
CC reticulum. Translocation from the nucleus to the cytoplasm is
CC stimulated in presence of nitric oxide (NO) and function in a
CC CRM1-dependent manner, possibly as a consequence of demasking a
CC nuclear export signal (amino acid position 64-80). S-nitrosylation
CC at Cys-93 and Cys-310 regulates its nuclear-cytosolic shuttling.
CC Ubiquitinated form is localized predominantly in the cytoplasm.
CC -!- SUBCELLULAR LOCATION: DNA-(apurinic or apyrimidinic site) lyase,
CC mitochondrial: Mitochondrion. Note=The cleaved APEX2 is only
CC detected in mitochondria (By similarity). Translocation from the
CC cytoplasm to the mitochondria is mediated by ROS signaling and
CC cleavage mediated by granzyme A. Tom20-dependent translocated
CC mitochondrial APEX1 level is significantly increased after
CC genotoxic stress.
CC -!- INDUCTION: Up-regulated in presence of reactive oxygen species
CC (ROS), like bleomycin, H(2)O(2) and phenazine methosulfate.
CC -!- DOMAIN: The N-terminus contains the redox activity while the C-
CC terminus exerts the DNA AP-endodeoxyribonuclease activity; both
CC function are independent in their actions. An unconventional
CC mitochondrial targeting sequence (MTS) is harbored within the C-
CC terminus, that appears to be masked by the N-terminal sequence
CC containing the nuclear localization signal (NLS), that probably
CC blocks the interaction between the MTS and Tom proteins.
CC -!- PTM: Phosphorylated. Phosphorylation by kinase PKC or casein
CC kinase CK2 results in enhanced redox activity that stimulates
CC binding of the FOS/JUN AP-1 complex to its cognate binding site.
CC AP-endodeoxyribonuclease activity is not affected by CK2-mediated
CC phosphorylation. Phosphorylation of Thr-233 by CDK5 reduces AP-
CC endodeoxyribonuclease activity resulting in accumulation of DNA
CC damage and contributing to neuronal death.
CC -!- PTM: Acetylated on Lys-6 and Lys-7. Acetylation is increased by
CC the transcriptional coactivator EP300 acetyltransferase, genotoxic
CC agents like H(2)O(2) and methyl methanesulfonate (MMS).
CC Acetylation increases its binding affinity to the negative calcium
CC response element (nCaRE) DNA promoter. The acetylated form induces
CC a stronger binding of YBX1 to the Y-box sequence in the MDR1
CC promoter than the unacetylated form. Deacetylated on lysines. Lys-
CC 6 and Lys-7 are deacetylated by SIRT1.
CC -!- PTM: Cleaved at Lys-31 by granzyme A to create the mitochondrial
CC form; leading in reduction of binding to DNA, AP endodeoxynuclease
CC activity, redox activation of transcription factors and to
CC enhanced cell death. Cleaved by granzyme K; leading to
CC intracellular ROS accumulation and enhanced cell death after
CC oxidative stress.
CC -!- PTM: Cys-65 and Cys-93 are nitrosylated in response to nitric
CC oxide (NO) and lead to the exposure of the nuclear export signal
CC (NES).
CC -!- PTM: Ubiquitinated by MDM2; leading to translocation to the
CC cytoplasm and proteasomal degradation.
CC -!- MISCELLANEOUS: Extract of mitochondria, but not of nuclei or
CC cytosol, cleaves recombinant APEX1 to generate a mitochondrial
CC APEX1-sized product (By similarity). The specific activity of the
CC cleaved mitochondrial endodeoxyribonuclease appeared to be about
CC 3-fold higher than that of the full-length form.
CC -!- SIMILARITY: Belongs to the DNA repair enzymes AP/ExoA family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/apex/";
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DR EMBL; X59764; CAA42437.1; -; mRNA.
DR EMBL; M80261; AAA58371.1; -; mRNA.
DR EMBL; D90373; BAA14381.1; -; mRNA.
DR EMBL; S43127; AAB22977.1; -; mRNA.
DR EMBL; M81955; AAA58372.1; -; mRNA.
DR EMBL; M92444; AAA58629.1; -; Genomic_DNA.
DR EMBL; X66133; CAA46925.1; -; Genomic_DNA.
DR EMBL; D13370; BAA02633.1; -; Genomic_DNA.
DR EMBL; U79268; AAB50212.1; -; mRNA.
DR EMBL; BT007236; AAP35900.1; -; mRNA.
DR EMBL; AF488551; AAL86909.1; -; Genomic_DNA.
DR EMBL; AL355075; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC002338; AAH02338.1; -; mRNA.
DR EMBL; BC004979; AAH04979.1; -; mRNA.
DR EMBL; BC008145; AAH08145.1; -; mRNA.
DR EMBL; BC019291; AAH19291.1; -; mRNA.
DR EMBL; M99703; AAA58373.1; -; Genomic_DNA.
DR PIR; S23550; S23550.
DR RefSeq; NP_001231178.1; NM_001244249.1.
DR RefSeq; NP_001632.2; NM_001641.3.
DR RefSeq; NP_542379.1; NM_080648.2.
DR RefSeq; NP_542380.1; NM_080649.2.
DR RefSeq; XP_005267638.1; XM_005267581.1.
DR UniGene; Hs.73722; -.
DR PDB; 1BIX; X-ray; 2.20 A; A=32-318.
DR PDB; 1CQG; NMR; -; B=59-71.
DR PDB; 1CQH; NMR; -; B=59-71.
DR PDB; 1DE8; X-ray; 2.95 A; A/B=43-318.
DR PDB; 1DE9; X-ray; 3.00 A; A/B=43-318.
DR PDB; 1DEW; X-ray; 2.65 A; A/B=40-318.
DR PDB; 1E9N; X-ray; 2.20 A; A/B=1-318.
DR PDB; 1HD7; X-ray; 1.95 A; A=1-318.
DR PDB; 2ISI; X-ray; 2.76 A; A/B/C=2-317.
DR PDB; 2O3H; X-ray; 1.90 A; A=40-318.
DR PDB; 3U8U; X-ray; 2.15 A; A/B/C/D/E/F=1-318.
DR PDB; 4IEM; X-ray; 2.39 A; A/B/C/D=2-318.
DR PDBsum; 1BIX; -.
DR PDBsum; 1CQG; -.
DR PDBsum; 1CQH; -.
DR PDBsum; 1DE8; -.
DR PDBsum; 1DE9; -.
DR PDBsum; 1DEW; -.
DR PDBsum; 1E9N; -.
DR PDBsum; 1HD7; -.
DR PDBsum; 2ISI; -.
DR PDBsum; 2O3H; -.
DR PDBsum; 3U8U; -.
DR PDBsum; 4IEM; -.
DR DisProt; DP00007; -.
DR ProteinModelPortal; P27695; -.
DR SMR; P27695; 44-318.
DR DIP; DIP-6130N; -.
DR IntAct; P27695; 29.
DR MINT; MINT-119189; -.
DR STRING; 9606.ENSP00000216714; -.
DR BindingDB; P27695; -.
DR ChEMBL; CHEMBL5619; -.
DR DrugBank; DB04967; Lucanthone.
DR PhosphoSite; P27695; -.
DR DMDM; 113984; -.
DR PaxDb; P27695; -.
DR PeptideAtlas; P27695; -.
DR PRIDE; P27695; -.
DR DNASU; 328; -.
DR Ensembl; ENST00000216714; ENSP00000216714; ENSG00000100823.
DR Ensembl; ENST00000398030; ENSP00000381111; ENSG00000100823.
DR Ensembl; ENST00000555414; ENSP00000451979; ENSG00000100823.
DR Ensembl; ENST00000557344; ENSP00000452137; ENSG00000100823.
DR GeneID; 328; -.
DR KEGG; hsa:328; -.
DR UCSC; uc001vxg.3; human.
DR CTD; 328; -.
DR GeneCards; GC14P020924; -.
DR HGNC; HGNC:587; APEX1.
DR HPA; CAB004294; -.
DR HPA; CAB047307; -.
DR HPA; HPA002564; -.
DR MIM; 107748; gene.
DR neXtProt; NX_P27695; -.
DR PharmGKB; PA201059; -.
DR eggNOG; COG0708; -.
DR HOGENOM; HOG000034586; -.
DR HOVERGEN; HBG050531; -.
DR InParanoid; P27695; -.
DR KO; K10771; -.
DR OMA; HETKFPA; -.
DR OrthoDB; EOG7C8GJ6; -.
DR PhylomeDB; P27695; -.
DR BRENDA; 4.2.99.18; 2681.
DR Reactome; REACT_216; DNA Repair.
DR ChiTaRS; APEX1; human.
DR EvolutionaryTrace; P27695; -.
DR GeneWiki; APEX1; -.
DR GenomeRNAi; 328; -.
DR NextBio; 1347; -.
DR PMAP-CutDB; P27695; -.
DR PRO; PR:P27695; -.
DR ArrayExpress; P27695; -.
DR Bgee; P27695; -.
DR CleanEx; HS_APEX1; -.
DR CleanEx; HS_HAP1; -.
DR Genevestigator; P27695; -.
DR GO; GO:0005813; C:centrosome; IDA:HPA.
DR GO; GO:0005783; C:endoplasmic reticulum; TAS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0016607; C:nuclear speck; IDA:UniProtKB.
DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005840; C:ribosome; TAS:UniProtKB.
DR GO; GO:0005667; C:transcription factor complex; IEA:Ensembl.
DR GO; GO:0008408; F:3'-5' exonuclease activity; IDA:UniProtKB.
DR GO; GO:0031490; F:chromatin DNA binding; IDA:UniProtKB.
DR GO; GO:0003684; F:damaged DNA binding; IDA:UniProtKB.
DR GO; GO:0003906; F:DNA-(apurinic or apyrimidinic site) lyase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IDA:UniProtKB.
DR GO; GO:0016491; F:oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0004528; F:phosphodiesterase I activity; TAS:UniProtKB.
DR GO; GO:0004523; F:ribonuclease H activity; TAS:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0016890; F:site-specific endodeoxyribonuclease activity, specific for altered base; IDA:UniProtKB.
DR GO; GO:0003713; F:transcription coactivator activity; IDA:UniProtKB.
DR GO; GO:0003714; F:transcription corepressor activity; TAS:ProtInc.
DR GO; GO:0004844; F:uracil DNA N-glycosylase activity; TAS:ProtInc.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0006284; P:base-excision repair; TAS:Reactome.
DR GO; GO:0045454; P:cell redox homeostasis; IEA:Ensembl.
DR GO; GO:0071320; P:cellular response to cAMP; IEA:Ensembl.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0071375; P:cellular response to peptide hormone stimulus; IEA:Ensembl.
DR GO; GO:0080111; P:DNA demethylation; IDA:UniProtKB.
DR GO; GO:0006310; P:DNA recombination; IEA:UniProtKB-KW.
DR GO; GO:0014912; P:negative regulation of smooth muscle cell migration; IEA:Ensembl.
DR GO; GO:0045739; P:positive regulation of DNA repair; IDA:UniProtKB.
DR GO; GO:0043488; P:regulation of mRNA stability; IMP:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 3.60.10.10; -; 1.
DR InterPro; IPR004808; AP_endonuc_1.
DR InterPro; IPR020847; AP_endonuclease_F1_BS.
DR InterPro; IPR020848; AP_endonuclease_F1_CS.
DR InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR PANTHER; PTHR22748; PTHR22748; 1.
DR Pfam; PF03372; Exo_endo_phos; 1.
DR SUPFAM; SSF56219; SSF56219; 1.
DR TIGRFAMs; TIGR00633; xth; 1.
DR PROSITE; PS00726; AP_NUCLEASE_F1_1; 1.
DR PROSITE; PS00727; AP_NUCLEASE_F1_2; 1.
DR PROSITE; PS00728; AP_NUCLEASE_F1_3; 1.
DR PROSITE; PS51435; AP_NUCLEASE_F1_4; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Activator;
KW Cleavage on pair of basic residues; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disulfide bond; DNA damage;
KW DNA recombination; DNA repair; DNA-binding; Endonuclease;
KW Endoplasmic reticulum; Exonuclease; Hydrolase; Lyase; Magnesium;
KW Metal-binding; Mitochondrion; Nuclease; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Repressor; RNA-binding;
KW S-nitrosylation; Transcription; Transcription regulation;
KW Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 318 DNA-(apurinic or apyrimidinic site)
FT lyase.
FT /FTId=PRO_0000200010.
FT CHAIN 32 318 DNA-(apurinic or apyrimidinic site)
FT lyase, mitochondrial (By similarity).
FT /FTId=PRO_0000402572.
FT REGION 2 33 Necessary for interaction with YBX1,
FT binding to RNA, NPM1-dependent
FT association with rRNA, endoribonuclease
FT activity on abasic RNA and localization
FT in the nucleoli.
FT REGION 8 13 Nuclear localization signal (NLS).
FT REGION 23 33 Necessary for interaction with NPM1 and
FT for efficient rRNA binding.
FT REGION 64 80 Nuclear export signal (NES).
FT REGION 289 318 Mitochondrial targeting sequence (MTS).
FT ACT_SITE 171 171
FT ACT_SITE 210 210 Proton donor/acceptor.
FT METAL 70 70 Magnesium 1.
FT METAL 96 96 Magnesium 1.
FT METAL 210 210 Magnesium 2.
FT METAL 212 212 Magnesium 2.
FT METAL 308 308 Magnesium 1.
FT SITE 31 32 Cleavage; by granzyme A.
FT SITE 212 212 Transition state stabilizer.
FT SITE 283 283 Important for catalytic activity.
FT SITE 309 309 Interaction with DNA substrate.
FT MOD_RES 6 6 N6-acetyllysine; by EP300.
FT MOD_RES 7 7 N6-acetyllysine; by EP300.
FT MOD_RES 27 27 N6-acetyllysine.
FT MOD_RES 31 31 N6-acetyllysine.
FT MOD_RES 32 32 N6-acetyllysine.
FT MOD_RES 35 35 N6-acetyllysine.
FT MOD_RES 65 65 S-nitrosocysteine.
FT MOD_RES 93 93 S-nitrosocysteine.
FT MOD_RES 197 197 N6-acetyllysine.
FT MOD_RES 233 233 Phosphothreonine; by CDK5 (By
FT similarity).
FT MOD_RES 310 310 S-nitrosocysteine.
FT DISULFID 65 93 Probable.
FT VARIANT 51 51 Q -> H (in dbSNP:rs1048945).
FT /FTId=VAR_013455.
FT VARIANT 64 64 I -> V (in dbSNP:rs2307486).
FT /FTId=VAR_014823.
FT VARIANT 148 148 D -> E (in dbSNP:rs1130409).
FT /FTId=VAR_019790.
FT MUTAGEN 6 6 K->R: Lack of acetylation, does not
FT stimulate the YBX1-mediated MDR1 promoter
FT activity and alter nuclear subcellular
FT localization; when associated with R-7.
FT Does not inhibit interaction with HDAC1,
FT HDAC2 and HDAC3. Absence of increase in
FT nCaRE binding activity.
FT MUTAGEN 7 7 K->R: Lack of acetylation and does not
FT stimulate the YBX1-mediated MDR1 promoter
FT activity and alter nuclear subcellular
FT localization; when associated with R-6.
FT MUTAGEN 12 12 E->A: Reduces nuclear localization; when
FT associated with A-13.
FT MUTAGEN 13 13 D->A: Reduces nuclear localization; when
FT associated with A-12.
FT MUTAGEN 24 24 K->A: Enhances the interaction with
FT TOMM20. Inhibits rRNA binding,
FT interaction with NPM1, nuclear
FT localization and modulates its
FT endodeoxyribonuclease activity; when
FT associated with A-25; A-27; A-31 and A-
FT 32. Inhibits ubiquitination; when
FT associated with K-25 and K-27.
FT MUTAGEN 25 25 K->A: Enhances the interaction with
FT TOMM20. Inhibits rRNA binding,
FT interaction with NPM1, nuclear
FT localization and modulates its
FT endodeoxyribonuclease activity; when
FT associated with A-24; A-27; A-31 and A-
FT 32. Inhibits ubiquitination; when
FT associated with K-24 and K-27.
FT MUTAGEN 27 27 K->A: Enhances the interaction with
FT TOMM20. Inhibits rRNA binding,
FT interaction with NPM1, nuclear
FT localization and modulates its
FT endodeoyribonuclease activity; when
FT associated with A-24; A-25; A-31 and A-
FT 32. Inhibits ubiquitination; when
FT associated with K-24 and K-25.
FT MUTAGEN 31 31 K->A: Enhances the interaction with
FT TOMM20. Does not inhibit redox and AP
FT endodeoyribonuclease activities. Inhibits
FT rRNA binding, interaction with NPM1,
FT nuclear localization and modulates its
FT endodeoxyribonuclease activity; when
FT associated with A-24; A-25; A-27 and A-
FT 32. Reduces protection from granzyme A-
FT mediated cell death; when associated with
FT A-65 and A-210.
FT MUTAGEN 32 32 K->A: Inhibits rRNA binding, interaction
FT with NPM1, nuclear localization and
FT modulates its endodeoxyribonuclease
FT activity; when associated with A-24; A-
FT 25; A-27 and A-31.
FT MUTAGEN 65 65 C->A: Abolishes the redox activity. Does
FT not abolish the AP endodeoxyribonuclease
FT and phosphodiesterase activities. Reduces
FT protection from granzyme A-mediated cell
FT death; when associated with A-31 and A-
FT 210.
FT MUTAGEN 65 65 C->S: Does not abolish NO-induced
FT nitrosylation. Enhances NO-induced
FT nuclear export.
FT MUTAGEN 68 68 N->A: Nearly abolishes AP
FT endodeoxyribonuclease activity.
FT MUTAGEN 70 70 D->A: Strongly reduces AP
FT endodeoxyribonuclease activity.
FT MUTAGEN 93 93 C->A: Abolishes partially the redox
FT activity.
FT MUTAGEN 93 93 C->S: Does not abolish NO-induced
FT nitrosylation. Abolishes NO-induced
FT nitrosylation and translocation from the
FT nucleus to the cytoplasm; when associated
FT with S-310.
FT MUTAGEN 96 96 E->A: Lacks MYC CRD RNA cleavage
FT activity.
FT MUTAGEN 99 99 C->A: Does not abolish the redox
FT activity.
FT MUTAGEN 138 138 C->A: Does not abolish the redox
FT activity.
FT MUTAGEN 171 171 Y->A,F,H: Abolishes the AP
FT endodeoxyribonuclease activity.
FT MUTAGEN 208 208 C->A: Does not abolish the redox
FT activity.
FT MUTAGEN 210 210 D->A,N: Abolishes the AP
FT endodeoxyribonuclease activity. Reduces
FT protection from granzyme A-mediated cell
FT death; when associated with A-31 and A-
FT 65.
FT MUTAGEN 212 212 N->A: Abolishes AP endodeoxyribonuclease
FT activity.
FT MUTAGEN 212 212 N->Q,D: Decreases AP
FT endodeoxyribonuclease activity.
FT MUTAGEN 266 266 F->A: Strongly reduces AP
FT endodeoxyribonuclease activity.
FT MUTAGEN 283 283 D->A: Strongly reduces AP
FT endodeoxyribonuclease activity, but does
FT not affect RNA cleavage activity. Nearly
FT abolishes AP endodeoxyribonuclease
FT activity; when associated with A-308.
FT MUTAGEN 296 296 C->A: Does not abolish the redox
FT activity.
FT MUTAGEN 299 299 K->A: Reduces the interaction with
FT TOMM20. Abolishes localization in the
FT mitochondria; when associated with A-301.
FT MUTAGEN 301 301 R->A: Reduces the interaction with
FT TOMM20. Abolishes localization in the
FT mitochondria; when associated with A-299.
FT MUTAGEN 303 303 K->A: Reduces the interaction with
FT TOMM20.
FT MUTAGEN 308 308 D->A: Reduces AP endodeoxyribonuclease
FT activity. Nearly abolishes AP
FT endodeoxyribonuclease activity; when
FT associated with A-283.
FT MUTAGEN 309 309 H->N,S: Abolishes AP
FT endodeoxyribonuclease activity. Lacks MYC
FT CRD RNA cleavage activity.
FT MUTAGEN 310 310 C->A: Does not abolish the redox
FT activity.
FT MUTAGEN 310 310 C->S: Does not abolish NO-induced
FT nitrosylation. Abolishes NO-induced
FT nitrosylation and translocation from the
FT nucleus to the cytoplasm; when associated
FT with S-93.
FT CONFLICT 57 57 G -> A (in Ref. 2; AAA58371).
FT CONFLICT 306 306 G -> A (in Ref. 2; AAA58371).
FT STRAND 62 68
FT HELIX 72 77
FT HELIX 80 87
FT STRAND 90 95
FT HELIX 101 103
FT HELIX 106 110
FT HELIX 112 114
FT STRAND 116 120
FT STRAND 122 124
FT STRAND 126 128
FT STRAND 131 137
FT STRAND 140 145
FT HELIX 149 151
FT STRAND 152 154
FT STRAND 157 161
FT STRAND 166 171
FT HELIX 177 179
FT HELIX 182 200
FT STRAND 205 210
FT HELIX 217 219
FT TURN 223 225
FT STRAND 227 229
FT TURN 230 232
FT HELIX 234 246
FT STRAND 249 251
FT HELIX 252 256
FT STRAND 257 259
FT HELIX 270 272
FT HELIX 273 276
FT STRAND 283 287
FT HELIX 289 294
FT STRAND 295 300
FT STRAND 306 309
FT STRAND 312 316
SQ SEQUENCE 318 AA; 35555 MW; B88579C01BAF80C6 CRC64;
MPKRGKKGAV AEDGDELRTE PEAKKSKTAA KKNDKEAAGE GPALYEDPPD QKTSPSGKPA
TLKICSWNVD GLRAWIKKKG LDWVKEEAPD ILCLQETKCS ENKLPAELQE LPGLSHQYWS
APSDKEGYSG VGLLSRQCPL KVSYGIGDEE HDQEGRVIVA EFDSFVLVTA YVPNAGRGLV
RLEYRQRWDE AFRKFLKGLA SRKPLVLCGD LNVAHEEIDL RNPKGNKKNA GFTPQERQGF
GELLQAVPLA DSFRHLYPNT PYAYTFWTYM MNARSKNVGW RLDYFLLSHS LLPALCDSKI
RSKALGSDHC PITLYLAL
//

MIM 107748
*RECORD*
*FIELD* NO
107748
*FIELD* TI
*107748 APEX NUCLEASE 1; APEX1
;;APURINIC ENDONUCLEASE; APE; APE1;;
HUMAN APURINIC ENDONUCLEASE 1; HAP1;;
read moreAPURINIC/APYRIMIDINIC EXONUCLEASE;;
REDOX FACTOR 1; REF1
*FIELD* TX

DESCRIPTION

APEX nuclease, also called apurinic endonuclease (APE), is a DNA repair
enzyme having apurinic/apyrimidinic (AP) endonuclease,
3-prime,5-prime-exonuclease, DNA 3-prime repair diesterase, and DNA
3-prime-phosphatase activities. AP sites resulting from loss of bases
are the most frequent lesions occurring in vivo in cellular DNA. AP
sites are known to be produced by spontaneous hydrolysis, by various
chemicals and radiations, and by DNA glycosylases that remove particular
abnormal bases from DNA. The resulting abasic sites can block the
progress of the DNA replication apparatus and cause mutations. These
sites must be corrected to restore genetic integrity.

CLONING

Demple et al. (1991) cloned and analyzed cDNA encoding a major human
APE. The predicted APE protein, which contained probable nuclear
transport signals, was identified as a member of a family of DNA repair
enzymes found in lower organisms. See also Robson and Hickson (1991) and
Cheng et al. (1992). APE was identified by Xanthoudakis et al. (1992) as
a reductive activator of c-Fos (164810) and c-Jun (165160) transcription
factors. Okazaki et al. (1994) identified APE as a repressor of the
parathyroid hormone gene (PTH; 168450) that binds to the negative
Ca(2+)-response elements (nCaREs) in the PTH promoter.

By Northern hybridization experiments, Akiyama et al. (1994) showed that
the APEX gene is expressed ubiquitously in human cells.

GENE FUNCTION

Izumi et al. (1996) analyzed the activity of the APE1 promoter by
transient expression of a luciferase reporter gene in human, HeLa, and
TK6 cells. Two nCaRE-like sequences were identified in the promoter
segments responsible for inhibiting reporter gene expression.
Competitive electrophoretic mobility shift assay with HeLa nuclear
extract indicated that the nCaRE sequences of the APE1 and PTH genes are
recognized by the APE1 polypeptide. These results suggested that the
APE1 gene may be downregulated by its own product.

By electrophoretic mobility shift assay (EMSA) analysis, Jayaraman et
al. (1997) determined that the factor that they called Ref1 is a potent
activator of latent p53 protein by redox-dependent and -independent
means.

Chou and Cheng (2002) showed that APE1 has a DNA
3-prime,5-prime-exonuclease activity on mismatched deoxyribonucleotides
at the 3-prime termini of nicked or gapped DNA molecules. The activity
is more efficient at short-patch repair than long-patch repair. In
addition, the exonuclease activity of nuclear APE1 can remove the
anti-HIV nucleoside analogs AZT and D4T from the 3-prime terminus of a
nick more efficiently than can cytosolic exonucleases. Chou and Cheng
(2002) proposed that APE1 may be involved in reducing the cytotoxicity
and improving the therapeutic index of anti-HIV compounds belonging to
the chain terminator category.

To investigate the relevance of REF1 in the growth regulation of uterine
leiomyomas (150699), Orii et al. (2002) studied expression of REF1 in
the myometrium and uterine smooth muscle tumors. Using 3 antibodies
against different epitopes of REF1, 2 forms of REF1 protein were
detected. The abundance of the large form of REF1 was increased in
leiomyoma extracts relative to myometrial tissue extracts, and the large
form was dominant in cell lines derived from leiomyosarcomas. A single
mRNA transcript was detected in the same samples, leading the authors to
hypothesize that the differentially migrating forms are the result of
posttranslational modification(s). In vitro incubation of leiomyoma
tissue extract led to a shift from the large form to the small form, and
this conversion was inhibited by either protease or phosphatase
inhibitors. The relative abundance of the large form of REF1 correlated
with proliferating cell nuclear antigen levels, suggesting a correlation
with increased proliferation. The authors concluded that altered
posttranslational modification of REF1 is involved in uterine smooth
muscle tumorigenesis.

GZMA (140050) induces caspase-independent apoptosis in a characteristic
manner, except it causes a distinctive form of DNA damage:
single-stranded DNA nicking. A target of GZMA is the SET (600960)
complex, including HMGB2 (163906) and ANP32A (600832). Fan et al. (2003)
showed that APEX is also present in the SET complex and binds to GZMA.
GZMA cleaves APEX after lys31, destroying its known oxidative repair
functions. Silencing of APEX expression by RNA interference nearly
doubled specific cell lysis, with enhanced DNA nicking. Mutation
analysis indicated that lys31 is crucial for GZMA cleavage of APEX and
GZMA-induced cell death.

GENE STRUCTURE

Harrison et al. (1992) determined the sequence of the APE gene, which
contains 4 small introns (ranging from 130 to 566 bp) and 5 exons, the
first of which is untranslated. Consistent with the constitutive
expression of AP endonuclease activity observed in other studies, the
0.5 kb of DNA sequence upstream of APE revealed only a possible CCAAT
box and no other regulatory sites or a TATA box.

Akiyama et al. (1994) cloned the human APEX gene and showed that it
consists of 5 exons spanning 2.64 kb and exists as a single copy in the
haploid genome. The boundaries between exons and introns follow the
GT/AG rule. Akiyama et al. (1995) cloned the homologous gene in the
mouse and determined its complete sequence. The gene consists of 5 exons
and 4 introns spanning 2.21 kb, and the boundaries between exons and
introns follow the GT/AG rule. Akiyama et al. (1995) described the
transcription initiation sites, translation initiation and termination
sites, and the characteristics of the 5-prime flanking region.

MAPPING

With a primer pair based on the published sequence of the bovine cDNA
used in PCR, Zhao et al. (1992) amplified a 437-bp segment from human
DNA without amplifying mouse or hamster DNA in somatic cell hybrids. By
this method, they assigned the APE gene to chromosome 14. Using 2
contiguous APE genomic clones as probes and in situ hybridization, they
regionalized the assignment to 14q12, very near to the junction of bands
q11.2 and q12. Using in situ hybridization, Robson et al. (1992) mapped
the APE gene to 14q11.2-q12. Akiyama et al. (1994) confirmed this
localization by FISH. Using FISH, Akiyama et al. (1995) assigned the
Apex gene to mouse chromosome 14C2-D1.

MOLECULAR GENETICS

Hayward et al. (1999) found a common polymorphism, D148E, of the APEX
gene that had an allele frequency significantly different in sporadic
amyotrophic lateral sclerosis (ALS; 105400) patients compared with
controls. They concluded, however, that although it may play a small
role in the etiology of ALS, it is not a 'fundamental' component in most
cases.

Hadi et al. (2000) identified 7 allelic variants of the APEX gene
resulting in amino acid substitutions. Functional characterization
indicated that 3 of the substitutions, leu104 to arg, glu126 to asp, and
arg237 to ala, reduced APEX incision activity by about 40 to 60%. A
substitution at an active site aspartic acid, asp283 to gly, resulted in
only about 10% repair capacity. The most common substitution, asp148 to
glu, which was observed at an allele frequency of 0.38, had no impact on
endonuclease and DNA binding activities, nor did a more infrequent
gly306-to-ala substitution. A gly241-to-arg substitution, which was
predicted to slightly stabilize helix 9, resulted in somewhat enhanced
endonuclease activity relative to wildtype. Hadi et al. (2000) concluded
that the 4 reduced-function variants may represent low-penetrance
polymorphisms that associate with increased disease susceptibility.

ANIMAL MODEL

Xanthoudakis et al. (1996) generated Ref1 -/- mice. Unlike the healthy
heterozygotes, the homozygous deficient mice died during embryonic
development following blastocyst formation, shortly after the time of
implantation.

Raffoul et al. (2004) characterized Ape +/- mice. Heterozygotes were Ape
haploinsufficient, with a 40 to 50% reduction in Ape mRNA, protein, and
5-prime endonuclease activity in all tissues studied. G:U mismatch base
excision repair was reduced by 35% in liver and by 55% in testis, but no
effect was found in brain. The changes in base excision repair activity
correlated with changes in DNA polymerase-beta (174760) and AP site DNA
binding.

Huamani et al. (2004) found that the spontaneous mutation frequency was
elevated about 2-fold in liver and spleen of 3-month-old heterozygous
Apex mutant mice compared with the frequency in wildtype littermates.
The mutation frequency was additionally elevated for somatic tissues
from 9-month old Apex +/- mice. Genetic instability was delayed in
spermatogenic cells, but it was observed in 9-month-old Apex +/- mice
compared with 9-month-old wildtype mice.

*FIELD* RF
1. Akiyama, K.; Nagao, K.; Oshida, T.; Tsutsui, K.; Yoshida, M. C.;
Seki, S.: Cloning, sequence analysis, and chromosomal assignment
of the mouse Apex gene. Genomics 26: 63-69, 1995.

2. Akiyama, K.; Seki, S.; Oshida, T.; Yoshida, M. C.: Structure,
promoter analysis and chromosomal assignment of the human APEX gene. Biochim.
Biophys. Acta 1219: 15-25, 1994.

3. Cheng, X.; Bunville, J.; Patterson, T. A.: Nucleotide sequence
of a cDNA for an apurinic/apyrimidinic endonuclease from HeLa cells. Nucleic
Acids Res. 20: 370 only, 1992.

4. Chou, K.-M.; Cheng, Y.-C.: An exonucleolytic activity of human
apurinic/apyrimidinic endonuclease on 3-prime mispaired DNA. Nature 415:
655-659, 2002.

5. Demple, B.; Herman, T.; Chen, D. S.: Cloning and expression of
APE, the cDNA encoding the major human apurinic endonuclease: definition
of a family of DNA repair enzymes. Proc. Nat. Acad. Sci. 88: 11450-11454,
1991.

6. Fan, Z.; Beresford, P. J.; Zhang, D.; Xu, Z.; Novina, C. D.; Yoshida,
A.; Pommier, Y.; Lieberman, J.: Cleaving the oxidative repair protein
Ape I enhances cell death mediated by granzyme A. Nature Immun. 4:
145-153, 2003.

7. Hadi, M. Z.; Coleman, M. A.; Fidelis, K.; Mohrenweiser, H. W.;
Wilson, D. M., III.: Functional characterization of Ape1 variants
identified in the human population. Nucleic Acids Res. 28: 3871-3879,
2000.

8. Harrison, L.; Ascione, G.; Menninger, J. C.; Ward, D. C.; Demple,
B.: Human apurinic endonuclease gene (APE): structure and genomic
mapping (chromosome 14q11.2-12). Hum. Molec. Genet. 1: 677-680,
1992.

9. Hayward, C.; Colville, S.; Swingler, R. J.; Brock, D. J. H.: Molecular
genetic analysis of the APEX nuclease gene in amyotrophic lateral
sclerosis. Neurology 52: 1899-1901, 1999.

10. Huamani, J.; McMahan, C. A.; Herbert, D. C.; Reddick, R.; McCarrey,
J. R.; MacInnes, M. I.; Chen, D. J.; Walter, C. A.: Spontaneous mutagenesis
is enhanced in Apex heterozygous mice. Molec. Cell. Biol. 24: 8145-8153,
2004.

11. Izumi, T.; Henner, D.; Mitra, S.: Negative regulation of the
major human AP-endonuclease, a multifunctional protein. Biochemistry 35:
14679-14683, 1996.

12. Jayaraman, L.; Murthy, K. G. K.; Zhu, C.; Curran, T.; Xanthoudakis,
S.; Prives, C.: Identification of redox/repair protein Ref-1 as a
potent activator of p53. Genes Dev. 11: 558-570, 1997.

13. Okazaki, T.; Chung, U.; Nishishita, T.; Ebisu, S.; Usuda, S.;
Mishiro, S.; Xanthoudakis, S.; Igarashi, T.; Ogata, E.: A redox factor
protein, ref1, is involved in negative gene regulation by extracellular
calcium. J. Biol. Chem. 269: 27855-27862, 1994.

14. Orii, A.; Masutani, H.; Nikaido, T.; Zhai, Y.-L.; Kato, K.; Kariya,
M.; Konishi, I.; Yodoi, J.; Fujii, S.: Altered post-translational
modification of redox factor 1 protein in human uterine smooth muscle
tumors. J. Clin. Endocr. Metab. 87: 3754-3759, 2002.

15. Raffoul, J. J.; Cabelof, D. C.; Nakamura, J.; Meira, L. B.; Friedberg,
E. C.; Heydari, A. R.: Apurinic/apyrimidinic endonuclease (APE/REF-1)
haploinsufficient mice display tissue-specific differences in DNA
polymerase beta-dependent base excision repair. J. Biol. Chem. 279:
18425-18433, 2004.

16. Robson, C. N.; Hickson, I. D.: Isolation of cDNA clones encoding
a human apurinic/apyrimidinic endonuclease that corrects DNA repair
and mutagenesis defects in E. coli xth (exonuclease III) mutants. Nucleic
Acids Res. 19: 5519-5523, 1991.

17. Robson, C. N.; Hochhauser, D.; Craig, R.; Rack, K.; Buckle, V.
J.; Hickson, I. D.: Structure of the human DNA repair gene HAP1 and
its localisation to chromosome 14q11.2-12. Nucleic Acids Res. 20:
4417-4421, 1992.

18. Xanthoudakis, S.; Miao, G.; Wang, F.; Pan, Y. C.; Curran, T.:
Redox activation of Fos-Jun DNA binding activity is mediated by a
DNA repair enzyme. EMBO J. 11: 3323-3335, 1992.

19. Xanthoudakis, S.; Smeyne, R. J.; Wallace, J. D.; Curran, T.:
The redox/DNA repair protein, Ref-1, is essential for early embryonic
development in mice. Proc. Nat. Acad. Sci. 93: 8919-8923, 1996.

20. Zhao, B.; Grandy, D. K.; Hagerup, J. M.; Magenis, R. E.; Smith,
L.; Chauhan, B. C.; Henner, W. D.: The human gene for apurinic/apyrimidinic
endonuclease (HAP1): sequence and localization to chromosome 14 band
q12. Nucleic Acids Res. 20: 4097-4098, 1992.

*FIELD* CN
Victor A. McKusick - updated: 4/27/2006
Patricia A. Hartz - updated: 10/5/2004
Paul J. Converse - updated: 1/9/2003
John A. Phillips, III - updated: 1/9/2003
Paul J. Converse - updated: 2/6/2002
Paul J. Converse - updated: 6/2/2000
Ethylin Wang Jabs - updated: 11/11/1997

*FIELD* CD
Victor A. McKusick: 1/3/1992

*FIELD* ED
wwang: 04/23/2009
alopez: 5/2/2006
terry: 4/27/2006
mgross: 10/5/2004
alopez: 2/26/2003
mgross: 1/9/2003
alopez: 1/9/2003
carol: 5/29/2002
mgross: 2/6/2002
carol: 6/2/2000
dholmes: 1/23/1998
mark: 12/19/1997
mark: 11/20/1997
mark: 11/18/1997
davew: 6/8/1994
carol: 9/13/1993
carol: 2/2/1993
carol: 10/22/1992
carol: 10/9/1992
carol: 10/8/1992