ID   APEX2_HUMAN             Reviewed;         518 AA.
AC   Q9UBZ4; Q9Y5X7;
DT   30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2000, sequence version 1.
DT   27-MAR-2024, entry version 182.
DE   RecName: Full=DNA-(apurinic or apyrimidinic site) endonuclease 2;
DE            EC=3.1.11.2 {ECO:0000269|PubMed:16687656, ECO:0000269|PubMed:19443450, ECO:0000269|PubMed:32516598};
DE   AltName: Full=AP endonuclease XTH2;
DE   AltName: Full=APEX nuclease 2;
DE   AltName: Full=APEX nuclease-like 2;
DE   AltName: Full=Apurinic-apyrimidinic endonuclease 2;
DE            Short=AP endonuclease 2;
GN   Name=APEX2; Synonyms=APE2, APEXL2, XTH2;
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], FUNCTION, INTERACTION WITH PCNA, SUBCELLULAR
RP   LOCATION, TISSUE SPECIFICITY, AND DOMAIN.
RC   TISSUE=Leukemia;
RX   PubMed=11376153; DOI=10.1093/nar/29.11.2349;
RA   Tsuchimoto D., Sakai Y., Sakumi K., Nishioka K., Sasaki M., Fujiwara T.,
RA   Nakabeppu Y.;
RT   "Human APE2 protein is mostly localized in the nuclei and to some extent in
RT   the mitochondria, while nuclear APE2 is partly associated with
RT   proliferating cell nuclear antigen.";
RL   Nucleic Acids Res. 29:2349-2360(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Lung tumor;
RA   Luna L., Rognes T., Henriksen A.C., Bjoras M., Seeberg E.;
RT   "Putative human AP endonuclease XTH2.";
RL   Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Bone marrow;
RA   Akiyama K., Sarker A.H., Yao M., Tsutsui K., Seki S.;
RT   "cDNA cloning and characterization of human APEX nuclease-like 2 (APEXL2)
RT   protein.";
RL   Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Lung tumor;
RA   Hadi M.Z., Erzberger J.P., Ramirez M.H., Thelen M.P., Wilson D.M. III;
RL   Submitted (JAN-1999) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT CYS-141.
RG   NIEHS SNPs program;
RL   Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15772651; DOI=10.1038/nature03440;
RA   Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA   Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA   Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA   Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA   Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA   Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA   Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA   Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA   Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA   Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA   Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA   Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA   Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA   Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA   Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA   Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA   Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA   Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA   Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA   Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA   Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA   Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA   Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA   Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA   Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA   Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA   Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA   Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA   Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA   Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA   McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA   Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA   Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA   Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA   Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA   Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA   Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA   Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA   Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA   Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA   d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA   Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA   Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA   Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA   Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA   Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA   Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA   Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA   Rogers J., Bentley D.R.;
RT   "The DNA sequence of the human X chromosome.";
RL   Nature 434:325-337(2005).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Lung;
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   [8]
RP   FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP   PROPERTIES, AND MUTAGENESIS OF ASP-277.
RX   PubMed=16687656; DOI=10.1093/nar/gkl259;
RA   Burkovics P., Szukacsov V., Unk I., Haracska L.;
RT   "Human Ape2 protein has a 3'-5' exonuclease activity that acts
RT   preferentially on mismatched base pairs.";
RL   Nucleic Acids Res. 34:2508-2515(2006).
RN   [9]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [10]
RP   FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP   AND MUTAGENESIS OF TYR-396 AND PHE-397.
RX   PubMed=19443450; DOI=10.1093/nar/gkp357;
RA   Burkovics P., Hajdu I., Szukacsov V., Unk I., Haracska L.;
RT   "Role of PCNA-dependent stimulation of 3'-phosphodiesterase and 3'-5'
RT   exonuclease activities of human Ape2 in repair of oxidative DNA damage.";
RL   Nucleic Acids Res. 37:4247-4255(2009).
RN   [11]
RP   FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH PCNA, DOMAIN, AND
RP   MUTAGENESIS OF GLU-48; ASP-197 AND 396-TYR-PHE-397.
RX   PubMed=32516598; DOI=10.1016/j.molcel.2020.05.021;
RA   Alvarez-Quilon A., Wojtaszek J.L., Mathieu M.C., Patel T., Appel C.D.,
RA   Hustedt N., Rossi S.E., Wallace B.D., Setiaputra D., Adam S., Ohashi Y.,
RA   Melo H., Cho T., Gervais C., Munoz I.M., Grazzini E., Young J.T.F.,
RA   Rouse J., Zinda M., Williams R.S., Durocher D.;
RT   "Endogenous DNA 3' Blocks Are Vulnerabilities for BRCA1 and BRCA2
RT   Deficiency and Are Reversed by the APE2 Nuclease.";
RL   Mol. Cell 78:1152-1165.e8(2020).
RN   [12]
RP   VARIANTS TYR-269 AND HIS-392.
RX   PubMed=20843780; DOI=10.1093/nar/gkq750;
RA   Wang W., Shen P., Thiyagarajan S., Lin S., Palm C., Horvath R.,
RA   Klopstock T., Cutler D., Pique L., Schrijver I., Davis R.W., Mindrinos M.,
RA   Speed T.P., Scharfe C.;
RT   "Identification of rare DNA variants in mitochondrial disorders with
RT   improved array-based sequencing.";
RL   Nucleic Acids Res. 39:44-58(2011).
CC   -!- FUNCTION: Functions as a weak apurinic/apyrimidinic (AP)
CC       endodeoxyribonuclease in the DNA base excision repair (BER) pathway of
CC       DNA lesions induced by oxidative and alkylating agents
CC       (PubMed:16687656). Initiates repair of AP sites in DNA by catalyzing
CC       hydrolytic incision of the phosphodiester backbone immediately adjacent
CC       to the damage, generating a single-strand break with 5'-deoxyribose
CC       phosphate and 3'-hydroxyl ends. Also displays double-stranded DNA 3'-5'
CC       exonuclease, 3'-phosphodiesterase activities (PubMed:16687656,
CC       PubMed:19443450, PubMed:32516598). Shows robust 3'-5' exonuclease
CC       activity on 3'-recessed heteroduplex DNA and is able to remove
CC       mismatched nucleotides preferentially (PubMed:16687656,
CC       PubMed:19443450). Also exhibits 3'-5' exonuclease activity on a single
CC       nucleotide gap containing heteroduplex DNA and on blunt-ended
CC       substrates (PubMed:16687656). Shows fairly strong 3'-phosphodiesterase
CC       activity involved in the removal of 3'-damaged termini formed in DNA by
CC       oxidative agents (PubMed:16687656, PubMed:19443450). In the nucleus
CC       functions in the PCNA-dependent BER pathway (PubMed:11376153). Plays a
CC       role in reversing blocked 3' DNA ends, problematic lesions that
CC       preclude DNA synthesis (PubMed:32516598). Required for somatic
CC       hypermutation (SHM) and DNA cleavage step of class switch recombination
CC       (CSR) of immunoglobulin genes (By similarity). Required for proper cell
CC       cycle progression during proliferation of peripheral lymphocytes (By
CC       similarity). {ECO:0000250|UniProtKB:Q68G58,
CC       ECO:0000269|PubMed:11376153, ECO:0000269|PubMed:16687656,
CC       ECO:0000269|PubMed:19443450, ECO:0000269|PubMed:32516598}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Exonucleolytic cleavage in the 3'- to 5'-direction to yield
CC         nucleoside 5'-phosphates.; EC=3.1.11.2;
CC         Evidence={ECO:0000269|PubMed:16687656, ECO:0000269|PubMed:19443450,
CC         ECO:0000269|PubMed:32516598};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:P27695};
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC         Evidence={ECO:0000250|UniProtKB:P27695};
CC       Note=Probably binds two magnesium or manganese ions per subunit.
CC       {ECO:0000250|UniProtKB:P27695};
CC   -!- ACTIVITY REGULATION: 3'-5' exonuclease activity is activated by sodium
CC       and manganese (PubMed:16687656). 3'-5' exonuclease and 3'-
CC       phosphodiesterase activities are stimulated in presence of PCNA
CC       (PubMed:19443450). {ECO:0000269|PubMed:16687656,
CC       ECO:0000269|PubMed:19443450}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       pH dependence:
CC         Optimum pH is 6.0-8.0. {ECO:0000269|PubMed:16687656};
CC   -!- SUBUNIT: Interacts with PCNA; this interaction is triggered by reactive
CC       oxygen species and increased by misincorporation of uracil in nuclear
CC       DNA. {ECO:0000269|PubMed:11376153, ECO:0000269|PubMed:32516598}.
CC   -!- INTERACTION:
CC       Q9UBZ4; Q13064: MKRN3; NbExp=3; IntAct=EBI-742588, EBI-2340269;
CC       Q9UBZ4; Q63HK5: TSHZ3; NbExp=3; IntAct=EBI-742588, EBI-9053916;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00764,
CC       ECO:0000269|PubMed:11376153, ECO:0000269|PubMed:19443450}. Cytoplasm.
CC       Mitochondrion {ECO:0000305|PubMed:11376153}. Note=Together with PCNA,
CC       is redistributed in discrete nuclear foci in presence of oxidative DNA
CC       damaging agents. {ECO:0000269|PubMed:19443450}.
CC   -!- TISSUE SPECIFICITY: Highly expressed in brain and kidney. Weakly
CC       expressed in the fetal brain. {ECO:0000269|PubMed:11376153}.
CC   -!- DOMAIN: The PCNA interacting protein (PIP) box mediates interaction
CC       with PCNA and recruitment to DNA single-strand breaks.
CC       {ECO:0000269|PubMed:11376153, ECO:0000269|PubMed:32516598}.
CC   -!- SIMILARITY: Belongs to the DNA repair enzymes AP/ExoA family.
CC       {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC       URL="http://egp.gs.washington.edu/data/apex2/";
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DR   EMBL; AB049211; BAB13764.1; -; mRNA.
DR   EMBL; AJ011311; CAB45242.1; -; mRNA.
DR   EMBL; AB021260; BAA78422.1; -; mRNA.
DR   EMBL; AF119046; AAD43041.1; -; mRNA.
DR   EMBL; AY884244; AAW56941.1; -; Genomic_DNA.
DR   EMBL; AL020991; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC002959; AAH02959.1; -; mRNA.
DR   CCDS; CCDS14365.1; -.
DR   RefSeq; NP_055296.2; NM_014481.3.
DR   AlphaFoldDB; Q9UBZ4; -.
DR   SMR; Q9UBZ4; -.
DR   BioGRID; 118124; 33.
DR   IntAct; Q9UBZ4; 28.
DR   STRING; 9606.ENSP00000364126; -.
DR   iPTMnet; Q9UBZ4; -.
DR   PhosphoSitePlus; Q9UBZ4; -.
DR   BioMuta; APEX2; -.
DR   DMDM; 73921676; -.
DR   EPD; Q9UBZ4; -.
DR   jPOST; Q9UBZ4; -.
DR   MassIVE; Q9UBZ4; -.
DR   MaxQB; Q9UBZ4; -.
DR   PaxDb; 9606-ENSP00000364126; -.
DR   PeptideAtlas; Q9UBZ4; -.
DR   ProteomicsDB; 84104; -.
DR   Pumba; Q9UBZ4; -.
DR   Antibodypedia; 26902; 188 antibodies from 26 providers.
DR   DNASU; 27301; -.
DR   Ensembl; ENST00000374987.4; ENSP00000364126.3; ENSG00000169188.5.
DR   GeneID; 27301; -.
DR   KEGG; hsa:27301; -.
DR   MANE-Select; ENST00000374987.4; ENSP00000364126.3; NM_014481.4; NP_055296.2.
DR   UCSC; uc004dtz.5; human.
DR   AGR; HGNC:17889; -.
DR   CTD; 27301; -.
DR   DisGeNET; 27301; -.
DR   GeneCards; APEX2; -.
DR   HGNC; HGNC:17889; APEX2.
DR   HPA; ENSG00000169188; Low tissue specificity.
DR   MIM; 300773; gene.
DR   neXtProt; NX_Q9UBZ4; -.
DR   OpenTargets; ENSG00000169188; -.
DR   PharmGKB; PA38474; -.
DR   VEuPathDB; HostDB:ENSG00000169188; -.
DR   eggNOG; KOG1294; Eukaryota.
DR   GeneTree; ENSGT00530000063540; -.
DR   HOGENOM; CLU_010374_3_0_1; -.
DR   InParanoid; Q9UBZ4; -.
DR   OMA; SFWICPR; -.
DR   OrthoDB; 169291at2759; -.
DR   PhylomeDB; Q9UBZ4; -.
DR   TreeFam; TF328442; -.
DR   BRENDA; 4.2.99.18; 2681.
DR   PathwayCommons; Q9UBZ4; -.
DR   SignaLink; Q9UBZ4; -.
DR   BioGRID-ORCS; 27301; 59 hits in 782 CRISPR screens.
DR   ChiTaRS; APEX2; human.
DR   GenomeRNAi; 27301; -.
DR   Pharos; Q9UBZ4; Tbio.
DR   PRO; PR:Q9UBZ4; -.
DR   Proteomes; UP000005640; Chromosome X.
DR   RNAct; Q9UBZ4; Protein.
DR   Bgee; ENSG00000169188; Expressed in endometrium epithelium and 165 other cell types or tissues.
DR   ExpressionAtlas; Q9UBZ4; baseline and differential.
DR   GO; GO:0001650; C:fibrillar center; IDA:HPA.
DR   GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR   GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR   GO; GO:0003906; F:DNA-(apurinic or apyrimidinic site) endonuclease activity; IBA:GO_Central.
DR   GO; GO:0008311; F:double-stranded DNA 3'-5' DNA exonuclease activity; IBA:GO_Central.
DR   GO; GO:0004519; F:endonuclease activity; IEA:UniProtKB-KW.
DR   GO; GO:0008081; F:phosphoric diester hydrolase activity; IBA:GO_Central.
DR   GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR   GO; GO:0006284; P:base-excision repair; IBA:GO_Central.
DR   GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR   GO; GO:0006310; P:DNA recombination; IEA:UniProtKB-KW.
DR   CDD; cd09088; Ape2-like_AP-endo; 1.
DR   Gene3D; 3.60.10.10; Endonuclease/exonuclease/phosphatase; 1.
DR   InterPro; IPR004808; AP_endonuc_1.
DR   InterPro; IPR020847; AP_endonuclease_F1_BS.
DR   InterPro; IPR036691; Endo/exonu/phosph_ase_sf.
DR   InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR   InterPro; IPR010666; Znf_GRF.
DR   NCBIfam; TIGR00633; xth; 1.
DR   PANTHER; PTHR22748; AP ENDONUCLEASE; 1.
DR   PANTHER; PTHR22748:SF4; DNA-(APURINIC OR APYRIMIDINIC SITE) ENDONUCLEASE 2; 1.
DR   Pfam; PF03372; Exo_endo_phos; 1.
DR   Pfam; PF06839; zf-GRF; 1.
DR   SUPFAM; SSF56219; DNase I-like; 1.
DR   PROSITE; PS00726; AP_NUCLEASE_F1_1; 1.
DR   PROSITE; PS51435; AP_NUCLEASE_F1_4; 1.
DR   PROSITE; PS51999; ZF_GRF; 1.
DR   Genevisible; Q9UBZ4; HS.
PE   1: Evidence at protein level;
KW   Cell cycle; Cytoplasm; DNA damage; DNA recombination; DNA repair;
KW   DNA-binding; Endonuclease; Exonuclease; Hydrolase; Magnesium;
KW   Metal-binding; Mitochondrion; Nuclease; Nucleus; Reference proteome; Zinc;
KW   Zinc-finger.
FT   CHAIN           1..518
FT                   /note="DNA-(apurinic or apyrimidinic site) endonuclease 2"
FT                   /id="PRO_0000200014"
FT   ZN_FING         469..518
FT                   /note="GRF-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01343"
FT   REGION          355..407
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          390..397
FT                   /note="Required for the interaction and colocalization with
FT                   PCNA in nuclear foci in presence of oxidative-induced DNA
FT                   damaging agents"
FT                   /evidence="ECO:0000269|PubMed:11376153,
FT                   ECO:0000269|PubMed:32516598"
FT   ACT_SITE        156
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   ACT_SITE        197
FT                   /note="Proton donor/acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   ACT_SITE        304
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00764"
FT   BINDING         8
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00764"
FT   BINDING         48
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00764"
FT   BINDING         197
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00764"
FT   BINDING         199
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00764"
FT   BINDING         303
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00764"
FT   BINDING         304
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00764"
FT   BINDING         469
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01343"
FT   BINDING         472
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01343"
FT   BINDING         495
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01343"
FT   BINDING         509
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01343"
FT   SITE            199
FT                   /note="Transition state stabilizer"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   SITE            277
FT                   /note="Important for catalytic activity"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   SITE            304
FT                   /note="Interaction with DNA substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   VARIANT         141
FT                   /note="R -> C (in dbSNP:rs2301416)"
FT                   /evidence="ECO:0000269|Ref.5"
FT                   /id="VAR_023390"
FT   VARIANT         141
FT                   /note="R -> W (in dbSNP:rs2301416)"
FT                   /id="VAR_048261"
FT   VARIANT         269
FT                   /note="H -> Y (identified in a patient with mtDNA
FT                   maintenance disorders; dbSNP:rs145122391)"
FT                   /evidence="ECO:0000269|PubMed:20843780"
FT                   /id="VAR_064033"
FT   VARIANT         392
FT                   /note="N -> H (identified in a patient with mtDNA
FT                   maintenance disorders; dbSNP:rs201964062)"
FT                   /evidence="ECO:0000269|PubMed:20843780"
FT                   /id="VAR_064034"
FT   MUTAGEN         48
FT                   /note="E->Q: Abolished 3'-5' exonuclease activity; when
FT                   associated with Asn-197. Synthetic lethality in a BRCA1 or
FT                   BRCA2 mutant cell line background; when associated with
FT                   Asn-197."
FT                   /evidence="ECO:0000269|PubMed:32516598"
FT   MUTAGEN         197
FT                   /note="D->N: Abolished 3'-5' exonuclease activity; when
FT                   associated with Gln-48. Synthetic lethality in a BRCA1 or
FT                   BRCA2 mutant cell line background; when associated with
FT                   Gln-48."
FT                   /evidence="ECO:0000269|PubMed:32516598"
FT   MUTAGEN         269
FT                   /note="H->A: Abolishes AP endodeoxyribonuclease, 3'-5'
FT                   exonuclease activity and 3'-phosphodiesterase activities."
FT   MUTAGEN         277
FT                   /note="D->A: Abolishes AP endodeoxyribonuclease, 3'-5'
FT                   exonuclease activity and 3'-phosphodiesterase activities."
FT                   /evidence="ECO:0000269|PubMed:16687656"
FT   MUTAGEN         396..397
FT                   /note="YF->AA: Loss of interaction with PCNA."
FT                   /evidence="ECO:0000269|PubMed:32516598"
FT   MUTAGEN         396
FT                   /note="Y->A: Reduces 3'-5' exonuclease activity in presence
FT                   of PCNA. Does not abolish the 3'-5' exonuclease activity.
FT                   Does only partially redistributes together with PCNA in
FT                   nuclear foci in presence of oxidative-induced DNA damaging
FT                   agents."
FT                   /evidence="ECO:0000269|PubMed:19443450"
FT   MUTAGEN         397
FT                   /note="F->A: Reduces 3'-5' exonuclease activity in presence
FT                   of PCNA. Does not abolish the 3'-5' exonuclease activity.
FT                   Does only partially redistributes together with PCNA in
FT                   nuclear foci in presence of oxidative-induced DNA damaging
FT                   agents."
FT                   /evidence="ECO:0000269|PubMed:19443450"
FT   CONFLICT        399
FT                   /note="P -> S (in Ref. 4; AAD43041)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   518 AA;  57401 MW;  08464806153F8832 CRC64;
     MLRVVSWNIN GIRRPLQGVA NQEPSNCAAV AVGRILDELD ADIVCLQETK VTRDALTEPL
     AIVEGYNSYF SFSRNRSGYS GVATFCKDNA TPVAAEEGLS GLFATQNGDV GCYGNMDEFT
     QEELRALDSE GRALLTQHKI RTWEGKEKTL TLINVYCPHA DPGRPERLVF KMRFYRLLQI
     RAEALLAAGS HVIILGDLNT AHRPIDHWDA VNLECFEEDP GRKWMDSLLS NLGCQSASHV
     GPFIDSYRCF QPKQEGAFTC WSAVTGARHL NYGSRLDYVL GDRTLVIDTF QASFLLPEVM
     GSDHCPVGAV LSVSSVPAKQ CPPLCTRFLP EFAGTQLKIL RFLVPLEQSP VLEQSTLQHN
     NQTRVQTCQN KAQVRSTRPQ PSQVGSSRGQ KNLKSYFQPS PSCPQASPDI ELPSLPLMSA
     LMTPKTPEEK AVAKVVKGQA KTSEAKDEKE LRTSFWKSVL AGPLRTPLCG GHREPCVMRT
     VKKPGPNLGR RFYMCARPRG PPTDPSSRCN FFLWSRPS
//