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Details on Person UniProt:P27695 APEX1
| Class:Id | ReferenceGeneProduct:50120 |
|---|---|
| _chainChangeLog | initiator methionine:1 added on Sat February 7 2015;chain:2-318 added on Sat February 7 2015;chain:32-318 added on Sat February 7 2015;initiator methionine:1 for 50120 removed on Fri Nov 03 2023;initiator methionine: for 50120 added on Fri Nov 03 2023;initiator methionine: for 50120 removed on Fri Aug 15 2025;initiator methionine:1 for 50120 added on Fri Aug 15 2025 |
| _displayName | UniProt:P27695 APEX1 |
| _timestamp | 2025-08-15 21:58:50 |
| chain | initiator methionine:1 chain:2-318 chain:32-318 |
| checksum | B88579C01BAF80C6 |
| comment | FUNCTION Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 are DNA repair and redox regulation of transcriptional factors (PubMed:11118054, PubMed:11452037, PubMed:15831793, PubMed:18439621, PubMed:18579163, PubMed:21762700, PubMed:24079850, PubMed:8355688, PubMed:9108029, PubMed:9560228). Functions as an apurinic/apyrimidinic (AP) endodeoxyribonuclease in the base excision repair (BER) pathway of DNA lesions induced by oxidative and alkylating agents. Initiates repair of AP sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage, generating a single-strand break with 5'-deoxyribose phosphate and 3'-hydroxyl ends. Also incises at AP sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA regions of R-loop structures, and single-stranded RNA molecules (PubMed:15380100, PubMed:16617147, PubMed:18439621, PubMed:19123919, PubMed:19188445, PubMed:19934257, PubMed:20699270, PubMed:21762700, PubMed:24079850, PubMed:8932375, PubMed:8995436, PubMed:9804799). Operates at switch sites of immunoglobulin (Ig) constant regions where it mediates Ig isotype class switch recombination. Processes AP sites induced by successive action of AICDA and UNG. Generates staggered nicks in opposite DNA strands resulting in the formation of double-strand DNA breaks that are finally resolved via non-homologous end joining repair pathway (By similarity). Has 3'-5' exodeoxyribonuclease activity on mismatched deoxyribonucleotides at the 3' termini of nicked or gapped DNA molecules during short-patch BER (PubMed:11832948, PubMed:1719477). Possesses DNA 3' phosphodiesterase activity capable of removing lesions (such as phosphoglycolate and 8-oxoguanine) blocking the 3' side of DNA strand breaks (PubMed:15831793, PubMed:7516064). Also acts as an endoribonuclease involved in the control of single-stranded RNA metabolism. Plays a role in regulating MYC mRNA turnover by preferentially cleaving in between UA and CA dinucleotides of the MYC coding region determinant (CRD). In association with NMD1, plays a role in the rRNA quality control process during cell cycle progression (PubMed:19188445, PubMed:19401441, PubMed:21762700). Acts as a loading factor for POLB onto non-incised AP sites in DNA and stimulates the 5'-terminal deoxyribose 5'-phosphate (dRp) excision activity of POLB (PubMed:9207062). Exerts reversible nuclear redox activity to regulate DNA binding affinity and transcriptional activity of transcriptional factors by controlling the redox status of their DNA-binding domain, such as the FOS/JUN AP-1 complex after exposure to IR (PubMed:10023679, PubMed:11118054, PubMed:11452037, PubMed:18579163, PubMed:8355688, PubMed:9108029). Involved in calcium-dependent down-regulation of parathyroid hormone (PTH) expression by binding to negative calcium response elements (nCaREs). Together with HNRNPL or the dimer XRCC5/XRCC6, associates with nCaRE, acting as an activator of transcriptional repression (PubMed:11809897, PubMed:14633989, PubMed:8621488). May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation (PubMed:21496894). Stimulates the YBX1-mediated MDR1 promoter activity, when acetylated at Lys-6 and Lys-7, leading to drug resistance (PubMed:18809583). Plays a role in protection from granzyme-mediated cellular repair leading to cell death (PubMed:18179823). Binds DNA and RNA. Associates, together with YBX1, on the MDR1 promoter. Together with NPM1, associates with rRNA (PubMed:19188445, PubMed:19401441, PubMed:20699270).CATALYTIC ACTIVITY a deoxyribonucleotide-2'-deoxyribose-5'-monophosphate-DNA + H2O = a 5'-end 2'-deoxyribose-5'-monophosphate-DNA + a 3'-end 2'-deoxyribonucleotide-DNA + H(+)CATALYTIC ACTIVITY Exonucleolytic cleavage in the 3'- to 5'-direction to yield nucleoside 5'-phosphates.CATALYTIC ACTIVITY a 3'-end 2'-deoxyribonucleotide-3'-phosphoglycolate-DNA + H2O = 2-phosphoglycolate + a 3'-end 2'-deoxyribonucleotide-DNA + H(+)CATALYTIC ACTIVITY a 3'-end 2'-deoxyribonucleotide-8-oxoguanine-DNA + H2O = 8-oxo-dGMP + a 3'-end 2'-deoxyribonucleotide-DNA + H(+)COFACTOR Probably binds two magnesium or manganese ions per subunit.ACTIVITY REGULATION NPM1 stimulates endodeoxyribonuclease activity on double-stranded DNA with AP sites, but inhibits endoribonuclease activity on single-stranded RNA containing AP sites.BIOPHYSICOCHEMICAL PROPERTIES Monomer. Homodimer; disulfide-linked. Component of the SET complex, composed of at least APEX1, SET, ANP32A, HMGB2, NME1 and TREX1. Associates with the dimer XRCC5/XRCC6 in a DNA-dependent manner. Interacts with SIRT1; the interaction is increased in the context of genotoxic stress. Interacts with HDAC1, HDAC2 and HDAC3; the interactions are not dependent on the APEX1 acetylation status. Interacts with XRCC1; the interaction is induced by SIRT1 and increased with the APEX1 acetylated form. Interacts with NPM1 (via N-terminal domain); the interaction is RNA-dependent and decreases in hydrogen peroxide-damaged cells. Interacts (via N-terminus) with YBX1 (via C-terminus); the interaction is increased in presence of APEX1 acetylated at Lys-6 and Lys-7. Interacts with HNRNPL; the interaction is DNA-dependent. Interacts (via N-terminus) with KPNA1 and KPNA2. Interacts with TXN; the interaction stimulates the FOS/JUN AP-1 complex DNA-binding activity in a redox-dependent manner. Interacts with GZMA, KRT8, MDM2, PRDX6, PRPF19, RPLP0, TOMM20 and WDR77. Interacts with POLB (PubMed:26760506, PubMed:9207062). Binds to CDK5.INTERACTION Detected in the cytoplasm of B-cells stimulated to switch (By similarity). Colocalized with SIRT1 in the nucleus. Colocalized with YBX1 in nuclear speckles after genotoxic stress. Together with OGG1 is recruited to nuclear speckles in UVA-irradiated cells. Colocalized with nucleolin and NPM1 in the nucleolus. Its nucleolar localization is cell cycle dependent and requires active rRNA transcription. Colocalized with calreticulin in the endoplasmic reticulum. Translocation from the nucleus to the cytoplasm is stimulated in presence of nitric oxide (NO) and function in a CRM1-dependent manner, possibly as a consequence of demasking a nuclear export signal (amino acid position 64-80). S-nitrosylation at Cys-93 and Cys-310 regulates its nuclear-cytosolic shuttling. Ubiquitinated form is localized predominantly in the cytoplasm.SUBCELLULAR LOCATION The cleaved APEX2 is only detected in mitochondria (By similarity). Translocation from the cytoplasm to the mitochondria is mediated by ROS signaling and cleavage mediated by granzyme A. Tom20-dependent translocated mitochondrial APEX1 level is significantly increased after genotoxic stress.INDUCTION Up-regulated in presence of reactive oxygen species (ROS), like bleomycin, H(2)O(2) and phenazine methosulfate.DOMAIN The N-terminus contains the redox activity while the C-terminus exerts the DNA AP-endodeoxyribonuclease activity; both functions are independent in their actions. An unconventional mitochondrial targeting sequence (MTS) is harbored within the C-terminus, that appears to be masked by the N-terminal sequence containing the nuclear localization signal (NLS), that probably blocks the interaction between the MTS and Tom proteins.PTM Phosphorylated. Phosphorylation by kinase PKC or casein kinase CK2 results in enhanced redox activity that stimulates binding of the FOS/JUN AP-1 complex to its cognate binding site. AP-endodeoxyribonuclease activity is not affected by CK2-mediated phosphorylation. Phosphorylation of Thr-233 by CDK5 reduces AP-endodeoxyribonuclease activity resulting in accumulation of DNA damage and contributing to neuronal death.PTM Acetylated on Lys-6 and Lys-7. Acetylation is increased by the transcriptional coactivator EP300 acetyltransferase, genotoxic agents like H(2)O(2) and methyl methanesulfonate (MMS). Acetylation increases its binding affinity to the negative calcium response element (nCaRE) DNA promoter. The acetylated form induces a stronger binding of YBX1 to the Y-box sequence in the MDR1 promoter than the unacetylated form. Deacetylated on lysines. Lys-6 and Lys-7 are deacetylated by SIRT1.PTM Cleaved at Lys-31 by granzyme A to create the mitochondrial form; leading to reduction of binding to DNA, AP endodeoxynuclease activity, redox activation of transcription factors and to enhanced cell death. Cleaved by granzyme K; leading to intracellular ROS accumulation and enhanced cell death after oxidative stress.PTM Cys-65 and Cys-93 are nitrosylated in response to nitric oxide (NO) and lead to the exposure of the nuclear export signal (NES).PTM Ubiquitinated by MDM2; leading to translocation to the cytoplasm and proteasomal degradation.MISCELLANEOUS Extract of mitochondria, but not of nuclei or cytosol, cleaves recombinant APEX1 to generate a mitochondrial APEX1-sized product (By similarity). The specific activity of the cleaved mitochondrial endodeoxyribonuclease appears to be about 3-fold higher than that of the full-length form.SIMILARITY Belongs to the DNA repair enzymes AP/ExoA family. |
| description | recommendedName: DNA repair nuclease/redox regulator APEX1 ecNumber evidence="9 17 28 36"3.1.11.2 ecNumber evidence="48"3.1.21.- alternativeName: APEX nuclease shortName: APEN alternativeName: Apurinic-apyrimidinic endonuclease 1 shortName: AP endonuclease 1 shortName: APE-1 alternativeName: DNA-(apurinic or apyrimidinic site) endonuclease alternativeName: Redox factor-1 shortName: REF-1 component recommendedName: DNA repair nuclease/redox regulator APEX1, mitochondrial /component |
| geneName | APEX1 APE APE1 APEX APX HAP1 REF1 |
| identifier | P27695 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation Activator Cleavage on pair of basic residues Cytoplasm Direct protein sequencing Disulfide bond DNA damage DNA recombination DNA repair DNA-binding Endonuclease Endoplasmic reticulum Exonuclease Hydrolase Magnesium Metal-binding Mitochondrion Nuclease Nucleus Phosphoprotein Proteomics identification Reference proteome Repressor RNA-binding S-nitrosylation Transcription Transcription regulation Ubl conjugation |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9841277] Weiser, Joel [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9909836] Weiser, Joel, 2024-05-14 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9948485] Weiser, Joel, 2025-05-21 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 |
| name | APEX1 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8989966] ENSEMBL:ENSG00000100823 APEX1 [Homo sapiens] |
| secondaryIdentifier | APEX1_HUMAN Q969L5 Q99775 |
| sequenceLength | 318 |
| species | [Species:48887] Homo sapiens |
| (referenceEntity) | [EntityWithAccessionedSequence:50119] APEX1 [nucleoplasm] [Homo sapiens] |
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No pathways have been reviewed or authored by UniProt:P27695 APEX1 (50120)
