ID APEX1_PANPA Reviewed; 318 AA.
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 06-FEB-2007, sequence version 1.
DT 14-MAY-2014, entry version 47.
DE RecName: Full=DNA-(apurinic or apyrimidinic site) lyase;
DE AltName: Full=APEX nuclease;
DE AltName: Full=Apurinic-apyrimidinic endonuclease 1;
DE Short=AP endonuclease 1;
DE AltName: Full=REF-1;
DE AltName: Full=Redox factor-1;
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.
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
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).
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.
CC -!- COFACTOR: Magnesium. Can also utilize manganese. Probably binds
CC two magnesium or manganese ions per subunit (By similarity).
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 (By similarity).
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).
CC -!- SUBCELLULAR LOCATION: Nucleus. Nucleus, nucleolus (By similarity).
CC Nucleus speckle (By similarity). Endoplasmic reticulum (By
CC similarity). Cytoplasm (By similarity). 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 -!- 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).
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 -!- 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 -!- 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 -!- 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).
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) (By similarity).
CC -!- PTM: Ubiquitinated by MDM2; leading to translocation to the
CC cytoplasm and proteasomal degradation (By similarity).
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).
CC -!- SIMILARITY: Belongs to the DNA repair enzymes AP/ExoA family.
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DR EMBL; DQ977185; ABM54218.1; -; Genomic_DNA.
DR RefSeq; XP_003811777.1; XM_003811729.1.
DR RefSeq; XP_003811778.1; XM_003811730.1.
DR RefSeq; XP_003811779.1; XM_003811731.1.
DR ProteinModelPortal; A1YFZ3; -.
DR SMR; A1YFZ3; 40-318.
DR GeneID; 100987860; -.
DR KEGG; pps:100987860; -.
DR CTD; 328; -.
DR HOVERGEN; HBG050531; -.
DR KO; K10771; -.
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:0008408; F:3'-5' exonuclease activity; ISS:UniProtKB.
DR GO; GO:0031490; F:chromatin DNA binding; ISS:UniProtKB.
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:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; ISS:UniProtKB.
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:0000737; P:DNA catabolic process, endonucleolytic; ISS:GOC.
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:0090305; P:nucleic acid phosphodiester bond hydrolysis; ISS:GOC.
DR GO; GO:0055114; P:oxidation-reduction process; ISS:GOC.
DR GO; GO:0045739; P:positive regulation of DNA repair; 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:0006351; P:transcription, DNA-templated; IEA:UniProtKB-KW.
DR Gene3D; 188.8.131.52; -; 1.
DR InterPro; IPR004808; AP_endonuc_1.
DR InterPro; IPR020847; AP_endonuclease_F1_BS.
DR InterPro; IPR020848; AP_endonuclease_F1_CS.
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;
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 INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 318 DNA-(apurinic or apyrimidinic site)
FT CHAIN 32 318 DNA-(apurinic or apyrimidinic site)
FT lyase, mitochondrial.
FT REGION 2 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 (By similarity).
FT REGION 8 13 Nuclear localization signal (NLS) (By
FT REGION 23 33 Necessary for interaction with NPM1 and
FT for efficient rRNA binding (By
FT REGION 64 80 Nuclear export signal (NES) (By
FT REGION 289 318 Mitochondrial targeting sequence (MTS)
FT (By similarity).
FT ACT_SITE 171 171 By similarity.
FT ACT_SITE 210 210 Proton donor/acceptor (By similarity).
FT METAL 70 70 Magnesium 1 (By similarity).
FT METAL 96 96 Magnesium 1 (By similarity).
FT METAL 210 210 Magnesium 2 (By similarity).
FT METAL 212 212 Magnesium 2 (By similarity).
FT METAL 308 308 Magnesium 1 (By similarity).
FT SITE 31 32 Cleavage; by granzyme A (By similarity).
FT SITE 212 212 Transition state stabilizer (By
FT SITE 283 283 Important for catalytic activity (By
FT SITE 309 309 Interaction with DNA substrate (By
FT MOD_RES 6 6 N6-acetyllysine; by EP300 (By
FT MOD_RES 7 7 N6-acetyllysine; by EP300 (By
FT MOD_RES 27 27 N6-acetyllysine (By similarity).
FT MOD_RES 31 31 N6-acetyllysine (By similarity).
FT MOD_RES 32 32 N6-acetyllysine (By similarity).
FT MOD_RES 35 35 N6-acetyllysine (By similarity).
FT MOD_RES 65 65 S-nitrosocysteine; alternate (By
FT MOD_RES 93 93 S-nitrosocysteine; alternate (By
FT MOD_RES 197 197 N6-acetyllysine (By similarity).
FT MOD_RES 233 233 Phosphothreonine; by CDK5 (By
FT MOD_RES 310 310 S-nitrosocysteine (By similarity).
FT DISULFID 65 93 Alternate (By similarity).
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