APEX1_PANTR
ID APEX1_PANTR Reviewed; 318 AA.
AC A2T6Y4;
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 06-MAR-2007, sequence version 1.
DT 03-AUG-2022, entry version 112.
DE RecName: Full=DNA-(apurinic or apyrimidinic site) endonuclease;
DE EC=3.1.11.2 {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-(apurinic or apyrimidinic site) endonuclease, mitochondrial;
GN Name=APEX1; Synonyms=APE, APEX, BAP1, REF1;
OS Pan troglodytes (Chimpanzee).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pan.
OX NCBI_TaxID=9598;
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 a 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. Does also incise at
CC AP sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA
CC regions of R-loop structures, and single-stranded RNA molecules. Has a
CC 3'-5' exoribonuclease activity on mismatched deoxyribonucleotides at
CC the 3' termini of nicked or gapped DNA molecules during short-patch
CC BER. Possesses a DNA 3' phosphodiesterase activity capable of removing
CC lesions (such as phosphoglycolate) blocking the 3' side of DNA strand
CC breaks. May also play a role in the epigenetic regulation of gene
CC expression by participating in DNA demethylation. Acts as a loading
CC factor for POLB onto non-incised AP sites in DNA and stimulates the 5'-
CC terminal deoxyribose 5'-phosphate (dRp) excision activity of POLB.
CC Plays a role in the protection from granzymes-mediated cellular repair
CC leading to cell death. Also involved in the DNA cleavage step of class
CC switch recombination (CSR). On the other hand, APEX1 also exerts
CC reversible 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}.
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; Evidence={ECO:0000250};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000250};
CC Note=Probably binds two magnesium or manganese ions per subunit.
CC {ECO:0000250};
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. {ECO:0000250}.
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}.
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-(apurinic or apyrimidinic site)
CC endonuclease, mitochondrial]: Mitochondrion. Note=Translocation from
CC the 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 genotoxic
CC stress. The cleaved APEX2 is only detected in mitochondria (By
CC 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). {ECO:0000250}.
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}.
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}.
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}.
CC -!- PTM: Ubiquitinated by MDM2; leading to translocation to the cytoplasm
CC and proteasomal degradation. {ECO:0000250}.
CC -!- MISCELLANEOUS: The specific activity of the cleaved mitochondrial
CC endodeoxyribonuclease appeared 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}.
CC -!- SIMILARITY: Belongs to the DNA repair enzymes AP/ExoA family.
CC {ECO:0000305}.
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DR EMBL; DQ977332; ABM91939.1; -; Genomic_DNA.
DR RefSeq; NP_001074954.1; NM_001081485.1.
DR RefSeq; XP_009425631.1; XM_009427356.2.
DR RefSeq; XP_009425633.1; XM_009427358.1.
DR AlphaFoldDB; A2T6Y4; -.
DR BMRB; A2T6Y4; -.
DR SMR; A2T6Y4; -.
DR STRING; 9598.ENSPTRP00000010344; -.
DR PaxDb; A2T6Y4; -.
DR Ensembl; ENSPTRT00000011181; ENSPTRP00000010344; ENSPTRG00000006093.
DR GeneID; 465200; -.
DR KEGG; ptr:465200; -.
DR CTD; 328; -.
DR VGNC; VGNC:8393; APEX1.
DR eggNOG; KOG1294; Eukaryota.
DR GeneTree; ENSGT00530000063540; -.
DR HOGENOM; CLU_027539_1_3_1; -.
DR InParanoid; A2T6Y4; -.
DR OMA; WWSYRGR; -.
DR OrthoDB; 1105625at2759; -.
DR TreeFam; TF315048; -.
DR Proteomes; UP000002277; Chromosome 14.
DR Bgee; ENSPTRG00000006093; Expressed in fibroblast and 21 other 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: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:0008311; F:double-stranded DNA 3'-5' exodeoxyribonuclease activity; IBA:GO_Central.
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:0008081; F:phosphoric diester hydrolase activity; IBA:GO_Central.
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:0006284; P:base-excision repair; IBA:GO_Central.
DR GO; GO:0045454; P:cell redox homeostasis; IEA:Ensembl.
DR GO; GO:0000737; P:DNA catabolic process, endonucleolytic; 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 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; IPR036691; Endo/exonu/phosph_ase_sf.
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 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-(apurinic or apyrimidinic site) endonuclease"
FT /id="PRO_0000285547"
FT CHAIN 32..318
FT /note="DNA-(apurinic or apyrimidinic site) endonuclease,
FT mitochondrial"
FT /id="PRO_0000402809"
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
