Database: UniProt
Entry: A1YFZ3
LinkDB: A1YFZ3
Original site: A1YFZ3 
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   28-FEB-2018, entry version 66.
DE   RecName: Full=DNA-(apurinic or apyrimidinic site) lyase;
DE            EC=3.1.-.-;
DE            EC=;
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) lyase, mitochondrial;
GN   Name=APEX1; Synonyms=APE, APEX, BAP1, REF1;
OS   Pan paniscus (Pygmy chimpanzee) (Bonobo).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Pan.
OX   NCBI_TaxID=9597;
RN   [1]
RA   Nickel G.C., Tefft D.L., Trevarthen K., Funt J., Adams M.D.;
RT   "Positive selection in transcription factor genes on the human
RT   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 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 (By similarity). {ECO:0000250}.
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. {ECO:0000255|PROSITE-ProRule:PRU00764}.
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   -!- 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. {ECO:0000250}.
CC   -!- SUBUNIT: Monomer. Homodimer; disulfide-linked. Component of the
CC       SET complex, composed of at least APEX1, SET, ANP32A, HMGB2, NME1
CC       and TREX1. Associates with the dimer XRCC5/XRCC6 in a DNA-
CC       dependent manner. Interacts with SIRT1; the interaction is
CC       increased in the context of genotoxic stress. Interacts with
CC       HDAC1, HDAC2 and HDAC3; the interactions are not dependent on the
CC       APEX1 acetylation status. Interacts with XRCC1; the interaction is
CC       induced by SIRT1 and increased with the APEX1 acetylated form.
CC       Interacts with NPM1 (via N-terminal domain); the interaction is
CC       RNA-dependent and decreases in hydrogen peroxide-damaged cells.
CC       Interacts (via N-terminus) with YBX1 (via C-terminus); the
CC       interaction is increased in presence of APEX1 acetylated at Lys-6
CC       and Lys-7. Interacts with HNRNPL; the interaction is DNA-
CC       dependent. Interacts (via N-terminus) with KPNA1 and KPNA2.
CC       Interacts with TXN; the interaction stimulates the FOS/JUN AP-1
CC       complex DNA-binding activity in a redox-dependent manner.
CC       Interacts with GZMA, KRT8, MDM2, POLB, PRDX6, PRPF19, RPLP0,
CC       TOMM20 and WDR77. Binds to CDK5 (By similarity). {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Nucleus. Nucleus, nucleolus {ECO:0000250}.
CC       Nucleus speckle {ECO:0000255|PROSITE-ProRule:PRU00764}.
CC       Endoplasmic reticulum {ECO:0000250}. Cytoplasm
CC       {ECO:0000255|PROSITE-ProRule:PRU00764}. Note=Detected in the
CC       cytoplasm of B-cells stimulated to switch. Colocalized with SIRT1
CC       in the nucleus. Colocalized with YBX1 in nuclear speckles after
CC       genotoxic stress. Together with OGG1 is recruited to nuclear
CC       speckles in UVA-irradiated cells. Colocalized with nucleolin and
CC       NPM1 in the nucleolus. Its nucleolar localization is cell cycle
CC       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
CC       manner, possibly as a consequence of demasking a nuclear export
CC       signal (amino acid position 64-80). S-nitrosylation at Cys-93 and
CC       Cys-310 regulates its nuclear-cytosolic shuttling. Ubiquitinated
CC       form is localized predominantly in the cytoplasm (By similarity).
CC       {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: DNA-(apurinic or apyrimidinic site) lyase,
CC       mitochondrial: Mitochondrion. Note=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. The cleaved APEX2 is only detected in
CC       mitochondria (By similarity). {ECO:0000250}.
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 (By
CC       similarity). {ECO:0000250}.
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 in response to
CC       MPP(+)/MPTP (1-methyl-4-phenylpyridinium) reduces AP-
CC       endodeoxyribonuclease activity resulting in accumulation of DNA
CC       damage and contributing to neuronal death (By similarity).
CC       {ECO:0000250}.
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 (By similarity).
CC       {ECO:0000250}.
CC   -!- PTM: Cleaved at Lys-31 by granzyme A to create the mitochondrial
CC       form; leading in reduction of binding to DNA, AP
CC       endodeoxyribonuclease activity, redox activation of transcription
CC       factors and to enhanced cell death. Cleaved by granzyme K; leading
CC       to intracellular ROS accumulation and enhanced cell death after
CC       oxidative stress (By similarity). {ECO:0000250}.
CC   -!- PTM: Cys-69 and Cys-93 are nitrosylated in response to nitric
CC       oxide (NO) and lead to the exposure of the nuclear export signal
CC       (NES). {ECO:0000250}.
CC   -!- PTM: Ubiquitinated by MDM2; leading to translocation to the
CC       cytoplasm 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
CC       the full-length form. Extract of mitochondria, but not of nuclei
CC       or cytosol, cleaves recombinant APEX1 to generate a mitochondrial
CC       APEX1-sized product (By similarity). {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the DNA repair enzymes AP/ExoA family.
CC       {ECO:0000305}.
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   ProteinModelPortal; A1YFZ3; -.
DR   SMR; A1YFZ3; -.
DR   Ensembl; ENSPPAT00000054561; ENSPPAP00000031696; ENSPPAG00000038760.
DR   GeneID; 100987860; -.
DR   KEGG; pps:100987860; -.
DR   CTD; 328; -.
DR   HOVERGEN; HBG050531; -.
DR   KO; K10771; -.
DR   OrthoDB; EOG091G0FDG; -.
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:0140078; F:class I DNA-(apurinic or apyrimidinic site) lyase activity; IEA:UniProtKB-EC.
DR   GO; GO:0140080; F:class III/IV DNA-(apurinic or apyrimidinic site) lyase activity; IEA:UniProtKB-EC.
DR   GO; GO:0003684; F:damaged DNA binding; ISS:UniProtKB.
DR   GO; GO:0003906; F:DNA-(apurinic or apyrimidinic site) lyase 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:0008081; F:phosphoric diester hydrolase activity; 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: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   GO; GO:0006355; P:regulation of transcription, DNA-templated; IEA:UniProtKB-KW.
DR   GO; GO:0097698; P:telomere maintenance via base-excision repair; IEA:Ensembl.
DR   GO; GO:0006351; P:transcription, DNA-templated; IEA:UniProtKB-KW.
DR   Gene3D;; -; 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.
PE   3: Inferred from homology;
KW   Acetylation; Activator; Cleavage on pair of basic residues; Cytoplasm;
KW   Disulfide bond; DNA damage; DNA recombination; DNA repair;
KW   DNA-binding; Endonuclease; Endoplasmic reticulum; Exonuclease;
KW   Hydrolase; Lyase; Magnesium; Metal-binding; Mitochondrion; Nuclease;
KW   Nucleus; Phosphoprotein; Repressor; RNA-binding; S-nitrosylation;
KW   Transcription; Transcription regulation; Ubl conjugation.
FT   CHAIN         1    318       DNA-(apurinic or apyrimidinic site)
FT                                lyase.
FT                                /FTId=PRO_0000285546.
FT   CHAIN        32    318       DNA-(apurinic or apyrimidinic site)
FT                                lyase, mitochondrial.
FT                                /FTId=PRO_0000402808.
FT   REGION        1     33       Necessary for interaction with YBX1,
FT                                binding to RNA, association together with
FT                                NPM1 to rRNA, endoribonuclease activity
FT                                on abasic RNA and localization in the
FT                                nucleoli. {ECO:0000250}.
FT   REGION       23     33       Necessary for interaction with NPM1 and
FT                                for efficient rRNA binding.
FT                                {ECO:0000250}.
FT   REGION      289    318       Mitochondrial targeting sequence (MTS).
FT                                {ECO:0000250}.
FT   MOTIF         8     13       Nuclear localization signal (NLS).
FT                                {ECO:0000250}.
FT   MOTIF        64     80       Nuclear export signal (NES).
FT                                {ECO:0000250}.
FT   ACT_SITE    171    171       {ECO:0000250}.
FT   ACT_SITE    210    210       Proton donor/acceptor. {ECO:0000250}.
FT   METAL        70     70       Magnesium 1. {ECO:0000250}.
FT   METAL        96     96       Magnesium 1. {ECO:0000250}.
FT   METAL       210    210       Magnesium 2. {ECO:0000250}.
FT   METAL       212    212       Magnesium 2. {ECO:0000250}.
FT   METAL       308    308       Magnesium 1. {ECO:0000250}.
FT   SITE         31     32       Cleavage; by granzyme A. {ECO:0000250}.
FT   SITE        212    212       Transition state stabilizer.
FT                                {ECO:0000250}.
FT   SITE        283    283       Important for catalytic activity.
FT                                {ECO:0000250}.
FT   SITE        309    309       Interaction with DNA substrate.
FT                                {ECO:0000250}.
FT   MOD_RES       6      6       N6-acetyllysine; by EP300.
FT                                {ECO:0000250|UniProtKB:P27695}.
FT   MOD_RES       7      7       N6-acetyllysine; by EP300.
FT                                {ECO:0000250|UniProtKB:P27695}.
FT   MOD_RES      27     27       N6-acetyllysine.
FT                                {ECO:0000250|UniProtKB:P27695}.
FT   MOD_RES      31     31       N6-acetyllysine.
FT                                {ECO:0000250|UniProtKB:P27695}.
FT   MOD_RES      32     32       N6-acetyllysine.
FT                                {ECO:0000250|UniProtKB:P27695}.
FT   MOD_RES      35     35       N6-acetyllysine.
FT                                {ECO:0000250|UniProtKB:P27695}.
FT   MOD_RES      54     54       Phosphoserine.
FT                                {ECO:0000250|UniProtKB:P27695}.
FT   MOD_RES      65     65       S-nitrosocysteine; alternate.
FT                                {ECO:0000250|UniProtKB:P27695}.
FT   MOD_RES      93     93       S-nitrosocysteine; alternate.
FT                                {ECO:0000250|UniProtKB:P27695}.
FT   MOD_RES     197    197       N6-acetyllysine.
FT                                {ECO:0000250|UniProtKB:P27695}.
FT   MOD_RES     233    233       Phosphothreonine; by CDK5.
FT                                {ECO:0000250|UniProtKB:P28352}.
FT   MOD_RES     310    310       S-nitrosocysteine.
FT                                {ECO:0000250|UniProtKB:P27695}.
FT   DISULFID     65     93       Alternate. {ECO:0000250}.
SQ   SEQUENCE   318 AA;  35569 MW;  B943A23BF487B5D3 CRC64;
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