ID   APEX1_PANPA             Reviewed;         318 AA.
AC   A1YFZ3;
DT   01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT   06-FEB-2007, sequence version 1.
DT   27-MAR-2024, entry version 93.
DE   RecName: Full=DNA repair nuclease/redox regulator APEX1;
DE            EC=3.1.11.2 {ECO:0000250|UniProtKB:P27695};
DE            EC=3.1.21.- {ECO:0000250|UniProtKB:P27695};
DE   AltName: Full=APEX nuclease;
DE            Short=APEN;
DE   AltName: Full=Apurinic-apyrimidinic endonuclease 1;
DE            Short=AP endonuclease 1;
DE   AltName: Full=REF-1;
DE   AltName: Full=Redox factor-1;
DE   Contains:
DE     RecName: Full=DNA repair nuclease/redox regulator APEX1, mitochondrial;
GN   Name=APEX1; Synonyms=APE, APEX, BAP1, REF1;
OS   Pan paniscus (Pygmy chimpanzee) (Bonobo).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Pan.
OX   NCBI_TaxID=9597;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Nickel G.C., Tefft D.L., Trevarthen K., Funt J., Adams M.D.;
RT   "Positive selection in transcription factor genes on the human lineage.";
RL   Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: Multifunctional protein that plays a central role in the
CC       cellular response to oxidative stress. The two major activities of
CC       APEX1 are DNA repair and redox regulation of transcriptional factors.
CC       Functions as an apurinic/apyrimidinic (AP) endodeoxyribonuclease in the
CC       DNA base excision repair (BER) pathway of DNA lesions induced by
CC       oxidative and alkylating agents. Initiates repair of AP sites in DNA by
CC       catalyzing hydrolytic incision of the phosphodiester backbone
CC       immediately adjacent to the damage, generating a single-strand break
CC       with 5'-deoxyribose phosphate and 3'-hydroxyl ends. Also incises at AP
CC       sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA regions
CC       of R-loop structures, and single-stranded RNA molecules. Has 3'-5'
CC       exoribonuclease activity on mismatched deoxyribonucleotides at the 3'
CC       termini of nicked or gapped DNA molecules during short-patch BER.
CC       Possesses DNA 3' phosphodiesterase activity capable of removing lesions
CC       (such as phosphoglycolate) blocking the 3' side of DNA strand breaks.
CC       May also play a role in the epigenetic regulation of gene expression by
CC       participating in DNA demethylation. Acts as a loading factor for POLB
CC       onto non-incised AP sites in DNA and stimulates the 5'-terminal
CC       deoxyribose 5'-phosphate (dRp) excision activity of POLB. Plays a role
CC       in the protection from granzyme-mediated cellular repair leading to
CC       cell death. Also involved in the DNA cleavage step of class switch
CC       recombination (CSR). On the other hand, APEX1 also exerts reversible
CC       nuclear redox activity to regulate DNA binding affinity and
CC       transcriptional activity of transcriptional factors by controlling the
CC       redox status of their DNA-binding domain, such as the FOS/JUN AP-1
CC       complex after exposure to IR. Involved in calcium-dependent down-
CC       regulation of parathyroid hormone (PTH) expression by binding to
CC       negative calcium response elements (nCaREs). Together with HNRNPL or
CC       the dimer XRCC5/XRCC6, associates with nCaRE, acting as an activator of
CC       transcriptional repression. Stimulates the YBX1-mediated MDR1 promoter
CC       activity, when acetylated at Lys-6 and Lys-7, leading to drug
CC       resistance. Acts also as an endoribonuclease involved in the control of
CC       single-stranded RNA metabolism. Plays a role in regulating MYC mRNA
CC       turnover by preferentially cleaving in between UA and CA dinucleotides
CC       of the MYC coding region determinant (CRD). In association with NMD1,
CC       plays a role in the rRNA quality control process during cell cycle
CC       progression. Associates, together with YBX1, on the MDR1 promoter.
CC       Together with NPM1, associates with rRNA. Binds DNA and RNA (By
CC       similarity). {ECO:0000250|UniProtKB:P27695}.
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:0000250|UniProtKB:P27695};
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: NPM1 stimulates endodeoxyribonuclease activity on
CC       double-stranded DNA with AP sites, but inhibits endoribonuclease
CC       activity on single-stranded RNA containing AP sites.
CC       {ECO:0000250|UniProtKB:P27695}.
CC   -!- SUBUNIT: Monomer. Homodimer; disulfide-linked. Component of the SET
CC       complex, composed of at least APEX1, SET, ANP32A, HMGB2, NME1 and
CC       TREX1. Associates with the dimer XRCC5/XRCC6 in a DNA-dependent manner.
CC       Interacts with SIRT1; the interaction is increased in the context of
CC       genotoxic stress. Interacts with HDAC1, HDAC2 and HDAC3; the
CC       interactions are not dependent on the APEX1 acetylation status.
CC       Interacts with XRCC1; the interaction is induced by SIRT1 and increased
CC       with the APEX1 acetylated form. Interacts with NPM1 (via N-terminal
CC       domain); the interaction is RNA-dependent and decreases in hydrogen
CC       peroxide-damaged cells. Interacts (via N-terminus) with YBX1 (via C-
CC       terminus); the interaction is increased in presence of APEX1 acetylated
CC       at Lys-6 and Lys-7. Interacts with HNRNPL; the interaction is DNA-
CC       dependent. Interacts (via N-terminus) with KPNA1 and KPNA2. Interacts
CC       with TXN; the interaction stimulates the FOS/JUN AP-1 complex DNA-
CC       binding activity in a redox-dependent manner. Interacts with GZMA,
CC       KRT8, MDM2, POLB, PRDX6, PRPF19, RPLP0, TOMM20 and WDR77. Binds to CDK5
CC       (By similarity). {ECO:0000250|UniProtKB:P27695}.
CC   -!- SUBCELLULAR LOCATION: Nucleus. Nucleus, nucleolus {ECO:0000250}.
CC       Nucleus speckle {ECO:0000255|PROSITE-ProRule:PRU00764}. Endoplasmic
CC       reticulum {ECO:0000250}. Cytoplasm {ECO:0000255|PROSITE-
CC       ProRule:PRU00764}. Note=Detected in the cytoplasm of B-cells stimulated
CC       to switch. Colocalized with SIRT1 in the nucleus. Colocalized with YBX1
CC       in nuclear speckles after genotoxic stress. Together with OGG1 is
CC       recruited to nuclear speckles in UVA-irradiated cells. Colocalized with
CC       nucleolin and NPM1 in the nucleolus. Its nucleolar localization is cell
CC       cycle dependent and requires active rRNA transcription (By similarity).
CC       Colocalized with calreticulin in the endoplasmic reticulum.
CC       Translocation from the nucleus to the cytoplasm is stimulated in
CC       presence of nitric oxide (NO) and function in a CRM1-dependent manner,
CC       possibly as a consequence of demasking a nuclear export signal (amino
CC       acid position 64-80). S-nitrosylation at Cys-93 and Cys-310 regulates
CC       its nuclear-cytosolic shuttling. Ubiquitinated form is localized
CC       predominantly in the cytoplasm (By similarity). {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: [DNA repair nuclease/redox regulator APEX1,
CC       mitochondrial]: Mitochondrion. Note=Translocation from the cytoplasm to
CC       the mitochondria is mediated by ROS signaling and cleavage mediated by
CC       granzyme A. Tom20-dependent translocated mitochondrial APEX1 level is
CC       significantly increased after genotoxic stress. The cleaved APEX2 is
CC       only detected in mitochondria (By similarity). {ECO:0000250}.
CC   -!- DOMAIN: The N-terminus contains the redox activity while the C-terminus
CC       exerts the DNA AP-endodeoxyribonuclease activity; both function are
CC       independent in their actions. An unconventional mitochondrial targeting
CC       sequence (MTS) is harbored within the C-terminus, that appears to be
CC       masked by the N-terminal sequence containing the nuclear localization
CC       signal (NLS), that probably blocks the interaction between the MTS and
CC       Tom proteins (By similarity). {ECO:0000250}.
CC   -!- PTM: Phosphorylated. Phosphorylation by kinase PKC or casein kinase CK2
CC       results in enhanced redox activity that stimulates binding of the
CC       FOS/JUN AP-1 complex to its cognate binding site. AP-
CC       endodeoxyribonuclease activity is not affected by CK2-mediated
CC       phosphorylation. Phosphorylation of Thr-233 by CDK5 in response to
CC       MPP(+)/MPTP (1-methyl-4-phenylpyridinium) reduces AP-
CC       endodeoxyribonuclease activity resulting in accumulation of DNA damage
CC       and contributing to neuronal death (By similarity).
CC       {ECO:0000250|UniProtKB:P27695}.
CC   -!- PTM: Acetylated on Lys-6 and Lys-7. Acetylation is increased by the
CC       transcriptional coactivator EP300 acetyltransferase, genotoxic agents
CC       like H(2)O(2) and methyl methanesulfonate (MMS). Acetylation increases
CC       its binding affinity to the negative calcium response element (nCaRE)
CC       DNA promoter. The acetylated form induces a stronger binding of YBX1 to
CC       the Y-box sequence in the MDR1 promoter than the unacetylated form.
CC       Deacetylated on lysines. Lys-6 and Lys-7 are deacetylated by SIRT1 (By
CC       similarity). {ECO:0000250|UniProtKB:P27695}.
CC   -!- PTM: Cleaved at Lys-31 by granzyme A to create the mitochondrial form;
CC       leading in reduction of binding to DNA, AP endodeoxyribonuclease
CC       activity, redox activation of transcription factors and to enhanced
CC       cell death. Cleaved by granzyme K; leading to intracellular ROS
CC       accumulation and enhanced cell death after oxidative stress (By
CC       similarity). {ECO:0000250|UniProtKB:P27695}.
CC   -!- PTM: Cys-69 and Cys-93 are nitrosylated in response to nitric oxide
CC       (NO) and lead to the exposure of the nuclear export signal (NES).
CC       {ECO:0000250|UniProtKB:P27695}.
CC   -!- PTM: Ubiquitinated by MDM2; leading to translocation to the cytoplasm
CC       and proteasomal degradation. {ECO:0000250|UniProtKB:P27695}.
CC   -!- MISCELLANEOUS: The specific activity of the cleaved mitochondrial
CC       endodeoxyribonuclease appears to be about 3-fold higher than of the
CC       full-length form. Extract of mitochondria, but not of nuclei or
CC       cytosol, cleaves recombinant APEX1 to generate a mitochondrial APEX1-
CC       sized product (By similarity). {ECO:0000250|UniProtKB:P23196}.
CC   -!- SIMILARITY: Belongs to the DNA repair enzymes AP/ExoA family.
CC       {ECO:0000305}.
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DR   EMBL; DQ977185; ABM54218.1; -; Genomic_DNA.
DR   RefSeq; XP_003811777.1; XM_003811729.2.
DR   RefSeq; XP_003811778.1; XM_003811730.2.
DR   RefSeq; XP_008962362.1; XM_008964114.1.
DR   AlphaFoldDB; A1YFZ3; -.
DR   BMRB; A1YFZ3; -.
DR   SMR; A1YFZ3; -.
DR   STRING; 9597.ENSPPAP00000031696; -.
DR   Ensembl; ENSPPAT00000054561.1; ENSPPAP00000031696.1; ENSPPAG00000038760.1.
DR   GeneID; 100987860; -.
DR   KEGG; pps:100987860; -.
DR   CTD; 328; -.
DR   eggNOG; KOG1294; Eukaryota.
DR   GeneTree; ENSGT00530000063540; -.
DR   OMA; WWSYRGR; -.
DR   OrthoDB; 161558at2759; -.
DR   Proteomes; UP000240080; Chromosome 14.
DR   Bgee; ENSPPAG00000038760; Expressed in adult mammalian kidney and 6 other cell types or tissues.
DR   GO; GO:0005813; C:centrosome; IEA:Ensembl.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR   GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR   GO; GO:0016607; C:nuclear speck; ISS:UniProtKB.
DR   GO; GO:0005730; C:nucleolus; ISS:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; ISS:UniProtKB.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR   GO; GO:0008408; F:3'-5' exonuclease activity; ISS:UniProtKB.
DR   GO; GO:0008296; F:3'-5'-DNA exonuclease activity; IEA:Ensembl.
DR   GO; GO:0031490; F:chromatin DNA binding; ISS:UniProtKB.
DR   GO; GO:0052720; F:class II DNA-(apurinic or apyrimidinic site) endonuclease activity; ISS:UniProtKB.
DR   GO; GO:0003684; F:damaged DNA binding; ISS:UniProtKB.
DR   GO; GO:0140431; F:DNA-(abasic site) binding; ISS:UniProtKB.
DR   GO; GO:0003906; F:DNA-(apurinic or apyrimidinic site) endonuclease activity; ISS:UniProtKB.
DR   GO; GO:0008309; F:double-stranded DNA exodeoxyribonuclease activity; IEA:Ensembl.
DR   GO; GO:0003691; F:double-stranded telomeric DNA binding; IEA:Ensembl.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0016491; F:oxidoreductase activity; ISS:UniProtKB.
DR   GO; GO:0090580; F:phosphodiesterase activity, acting on 3'-phosphoglycolate-terminated DNA strands; IEA:Ensembl.
DR   GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR   GO; GO:0016890; F:site-specific endodeoxyribonuclease activity, specific for altered base; ISS:UniProtKB.
DR   GO; GO:0003713; F:transcription coactivator activity; IEA:Ensembl.
DR   GO; GO:0045454; P:cell redox homeostasis; IEA:Ensembl.
DR   GO; GO:0006308; P:DNA catabolic process; IEA:Ensembl.
DR   GO; GO:0080111; P:DNA demethylation; ISS:UniProtKB.
DR   GO; GO:0006310; P:DNA recombination; IEA:UniProtKB-KW.
DR   GO; GO:0006281; P:DNA repair; ISS:UniProtKB.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR   GO; GO:0042981; P:regulation of apoptotic process; ISS:UniProtKB.
DR   GO; GO:0043488; P:regulation of mRNA stability; ISS:UniProtKB.
DR   GO; GO:0097698; P:telomere maintenance via base-excision repair; IEA:Ensembl.
DR   CDD; cd09087; Ape1-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; IPR020848; AP_endonuclease_F1_CS.
DR   InterPro; IPR036691; Endo/exonu/phosph_ase_sf.
DR   InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR   NCBIfam; TIGR00195; exoDNase_III; 1.
DR   NCBIfam; TIGR00633; xth; 1.
DR   PANTHER; PTHR22748; AP ENDONUCLEASE; 1.
DR   PANTHER; PTHR22748:SF6; DNA-(APURINIC OR APYRIMIDINIC SITE) ENDONUCLEASE; 1.
DR   Pfam; PF03372; Exo_endo_phos; 1.
DR   SUPFAM; SSF56219; DNase I-like; 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   3: Inferred from homology;
KW   Acetylation; Activator; Cleavage on pair of basic residues; Cytoplasm;
KW   Disulfide bond; DNA damage; DNA recombination; DNA repair; DNA-binding;
KW   Endonuclease; Endoplasmic reticulum; Exonuclease; Hydrolase; Magnesium;
KW   Metal-binding; Mitochondrion; Nuclease; Nucleus; Phosphoprotein;
KW   Reference proteome; Repressor; RNA-binding; S-nitrosylation; Transcription;
KW   Transcription regulation; Ubl conjugation.
FT   CHAIN           1..318
FT                   /note="DNA repair nuclease/redox regulator APEX1"
FT                   /id="PRO_0000285546"
FT   CHAIN           32..318
FT                   /note="DNA repair nuclease/redox regulator APEX1,
FT                   mitochondrial"
FT                   /id="PRO_0000402808"
FT   REGION          1..60
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1..33
FT                   /note="Necessary for interaction with YBX1, binding to RNA,
FT                   association together with NPM1 to rRNA, endoribonuclease
FT                   activity on abasic RNA and localization in the nucleoli"
FT                   /evidence="ECO:0000250"
FT   REGION          23..33
FT                   /note="Necessary for interaction with NPM1 and for
FT                   efficient rRNA binding"
FT                   /evidence="ECO:0000250"
FT   REGION          289..318
FT                   /note="Mitochondrial targeting sequence (MTS)"
FT                   /evidence="ECO:0000250"
FT   MOTIF           8..13
FT                   /note="Nuclear localization signal (NLS)"
FT                   /evidence="ECO:0000250"
FT   MOTIF           64..80
FT                   /note="Nuclear export signal (NES)"
FT                   /evidence="ECO:0000250"
FT   COMPBIAS        1..41
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        171
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        210
FT                   /note="Proton donor/acceptor"
FT                   /evidence="ECO:0000250"
FT   BINDING         70
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         96
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         210
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         212
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         308
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   SITE            31..32
FT                   /note="Cleavage; by granzyme A"
FT                   /evidence="ECO:0000250"
FT   SITE            212
FT                   /note="Transition state stabilizer"
FT                   /evidence="ECO:0000250"
FT   SITE            283
FT                   /note="Important for catalytic activity"
FT                   /evidence="ECO:0000250"
FT   SITE            309
FT                   /note="Interaction with DNA substrate"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         6
FT                   /note="N6-acetyllysine; by EP300"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   MOD_RES         7
FT                   /note="N6-acetyllysine; by EP300"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   MOD_RES         27
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   MOD_RES         31
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   MOD_RES         32
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   MOD_RES         35
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   MOD_RES         54
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   MOD_RES         65
FT                   /note="S-nitrosocysteine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   MOD_RES         93
FT                   /note="S-nitrosocysteine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   MOD_RES         197
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   MOD_RES         233
FT                   /note="Phosphothreonine; by CDK5"
FT                   /evidence="ECO:0000250|UniProtKB:P28352"
FT   MOD_RES         310
FT                   /note="S-nitrosocysteine"
FT                   /evidence="ECO:0000250|UniProtKB:P27695"
FT   DISULFID        65..93
FT                   /note="Alternate"
FT                   /evidence="ECO:0000250"
SQ   SEQUENCE   318 AA;  35569 MW;  B943A23BF487B5D3 CRC64;
     MPKRGKKGAV AEDGDELRTE PEAKKSKTAA KKNDKEAAGE GPALYEDPPD QKTSPSGKPA
     TLKICSWNVD GLRAWIKKKG LDWVKEEAPD ILCLQETKCS ENKLPAELQE LPGLSHQYWS
     APSDKEGYSG VGLLSRQCPL KVSYGIGEEE HDQEGRVIVA EFDSFVLVTA YVPNAGRGLV
     RLEYRQRWDE AFRKFLKGLA SRKPLVLCGD LNVAHEEIDL RNPKGNKKNA GFTPQERQGF
     GELLQAVPLA DSFRHLYPNT PYAYTFWTYM MNARSKNVGW RLDYFLLSHS LLPALCDSKI
     RSKALGSDHC PITLYLAL
//