APEX1_BOVIN
ID APEX1_BOVIN Reviewed; 318 AA.
AC P23196; Q0IIJ5;
DT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 03-AUG-2022, entry version 174.
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 Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 2-19.
RC TISSUE=Thymus;
RX PubMed=1708495; DOI=10.1093/nar/19.5.1087;
RA Robson C.N., Milne A.M., Pappin D.J.C., Hickson I.D.;
RT "Isolation of cDNA clones encoding an enzyme from bovine cells that repairs
RT oxidative DNA damage in vitro: homology with bacterial repair enzymes.";
RL Nucleic Acids Res. 19:1087-1092(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Hereford; TISSUE=Basal ganglia;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP PROTEIN SEQUENCE OF 2-23.
RC TISSUE=Thymus;
RX PubMed=2441359; DOI=10.1093/nar/15.14.5529;
RA Henner W.D., Kiker N.P., Jorgensen T.J., Munck J.-N.;
RT "Purification and amino-terminal amino acid sequence of an
RT apurinic/apyrimidinic endonuclease from calf thymus.";
RL Nucleic Acids Res. 15:5529-5544(1987).
RN [4]
RP PROTEIN SEQUENCE OF 34-38, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Liver;
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 [5]
RP 3D-STRUCTURE MODELING OF 40-318.
RX PubMed=15607727; DOI=10.1016/j.bbrc.2004.11.103;
RA Khurshid R., Salim A., Abbasi A.;
RT "Three-dimensional structure prediction of bovine AP lyase, BAP1:
RT prediction of interaction with DNA and alterations as a result of
RT Arg176->Ala, Asp282->Ala, and His308->Asn mutations.";
RL Biochem. Biophys. Res. Commun. 326:711-717(2005).
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, ECO:0000269|PubMed:16617147}.
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 -!- 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 {ECO:0000255|PROSITE-ProRule:PRU00764,
CC ECO:0000269|PubMed:16617147}. Nucleus, nucleolus {ECO:0000250}. Nucleus
CC speckle {ECO:0000255|PROSITE-ProRule:PRU00764}. Endoplasmic reticulum
CC {ECO:0000250}. Cytoplasm {ECO:0000255|PROSITE-ProRule:PRU00764}.
CC Note=Detected in the cytoplasm of B-cells stimulated to switch.
CC Colocalized with SIRT1 in the nucleus. Colocalized with YBX1 in nuclear
CC speckles after genotoxic stress. Together with OGG1 is recruited to
CC nuclear speckles in UVA-irradiated cells. Colocalized with nucleolin
CC and NPM1 in the nucleolus. Its nucleolar localization is cell cycle
CC dependent and requires active rRNA transcription. Colocalized with
CC calreticulin in the endoplasmic reticulum. Translocation from the
CC nucleus to the cytoplasm is stimulated in presence of nitric oxide (NO)
CC and function in a CRM1-dependent manner, possibly as a consequence of
CC demasking a nuclear export signal (amino acid position 64-80). S-
CC nitrosylation at Cys-93 and Cys-310 regulates its nuclear-cytosolic
CC shuttling. Ubiquitinated form is localized predominantly in the
CC cytoplasm.
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 (By similarity). The cleaved APEX2 is only detected in
CC mitochondria. {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: The mitochondrial form is expressed in liver (at
CC protein level). Thymus. {ECO:0000269|PubMed:16617147}.
CC -!- INDUCTION: By several DNA damaging agents.
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.
CC -!- SIMILARITY: Belongs to the DNA repair enzymes AP/ExoA family.
CC {ECO:0000305}.
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DR EMBL; X56685; CAA40014.1; -; mRNA.
DR EMBL; BC122610; AAI22611.1; -; mRNA.
DR PIR; S26830; S26830.
DR RefSeq; NP_788782.2; NM_176609.3.
DR AlphaFoldDB; P23196; -.
DR SMR; P23196; -.
DR STRING; 9913.ENSBTAP00000003559; -.
DR PaxDb; P23196; -.
DR PeptideAtlas; P23196; -.
DR PRIDE; P23196; -.
DR GeneID; 281630; -.
DR KEGG; bta:281630; -.
DR CTD; 328; -.
DR eggNOG; KOG1294; Eukaryota.
DR HOGENOM; CLU_027539_1_3_1; -.
DR InParanoid; P23196; -.
DR OrthoDB; 1105625at2759; -.
DR TreeFam; TF315048; -.
DR BRENDA; 4.2.99.18; 908.
DR Proteomes; UP000009136; Unplaced.
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; ISS:AgBase.
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:0003677; F:DNA binding; ISS:AgBase.
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:0046872; F:metal ion binding; ISS:AgBase.
DR GO; GO:0016491; F:oxidoreductase activity; ISS:UniProtKB.
DR GO; GO:0008081; F:phosphoric diester hydrolase activity; ISS:AgBase.
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; ISS:AgBase.
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:0042981; P:regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0043488; P:regulation of mRNA stability; ISS:UniProtKB.
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 1: Evidence at protein level;
KW Acetylation; Activator; Cleavage on pair of basic residues; Cytoplasm;
KW Direct protein sequencing; Disulfide bond; DNA damage; DNA recombination;
KW DNA repair; DNA-binding; Endonuclease; Endoplasmic reticulum; Exonuclease;
KW Hydrolase; Magnesium; Metal-binding; Mitochondrion; Nuclease; Nucleus;
KW Phosphoprotein; Reference proteome; Repressor; RNA-binding;
KW S-nitrosylation; Transcription; Transcription regulation; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:1708495,
FT ECO:0000269|PubMed:2441359"
FT CHAIN 2..318
FT /note="DNA-(apurinic or apyrimidinic site) endonuclease"
FT /id="PRO_0000200009"
FT CHAIN 32..318
FT /note="DNA-(apurinic or apyrimidinic site) endonuclease,
FT mitochondrial"
FT /id="PRO_0000402571"
FT REGION 1..59
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2..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"
FT CONFLICT 21..22
FT /note="PE -> LP (in Ref. 3; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 291
FT /note="V -> L (in Ref. 2; AAI22611)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 318 AA; 35570 MW; 40C733FBA2EA738D CRC64;
MPKRGKKGAV VEDAEEPKTE PEAKKSKAGA KKNEKEAVGE GAVLYEDPPD QKTSPSGKSA
TLKICSWNVD GLRAWIKKKG LDWVKEEAPD ILCLQETKCS ENKLPVELQE LSGLSHQYWS
APSDKEGYSG VGLLSRQCPL KVSYGIGEEE HDQEGRVIVA EYDAFVLVTA YVPNAGRGLV
RLEYRQRWDE AFRKFLKGLA SRKPLVLCGD LNVAHEEIDL RNPKGNKKNA GFTPQERQGF
GELLQAVPLT DSFRHLYPNT AYAYTFWTYM MNARSKNVGW RLDYFLLSQS VLPALCDSKI
RSKALGSDHC PITLYLAL
