A1YFZ3 (APEX1_PANPA) Reviewed, UniProtKB/Swiss-Prot
Last modified May 14, 2014. Version 47. History...
Names and origin
|Protein names||Recommended name:|
DNA-(apurinic or apyrimidinic site) lyase
Apurinic-apyrimidinic endonuclease 1
Short name=AP endonuclease 1
Cleaved into the following chain:
|Organism||Pan paniscus (Pygmy chimpanzee) (Bonobo)|
|Taxonomic identifier||9597 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Pan|
|Sequence length||318 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Inferred from homology|
General annotation (Comments)
Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 in DNA repair and redox regulation of transcriptional factors. Functions as a apurinic/apyrimidinic (AP) endodeoxyribonuclease in the DNA 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. Does also incise at AP sites in the DNA strand of DNA/RNA hybrids, single-stranded DNA regions of R-loop structures, and single-stranded RNA molecules. Has a 3'-5' exoribonuclease activity on mismatched deoxyribonucleotides at the 3' termini of nicked or gapped DNA molecules during short-patch BER. Possesses a DNA 3' phosphodiesterase activity capable of removing lesions (such as phosphoglycolate) blocking the 3' side of DNA strand breaks. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation. 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. Plays a role in the protection from granzymes-mediated cellular repair leading to cell death. Also involved in the DNA cleavage step of class switch recombination (CSR). On the other hand, APEX1 also 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. 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. Stimulates the YBX1-mediated MDR1 promoter activity, when acetylated at Lys-6 and Lys-7, leading to drug resistance. Acts also 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. Associates, together with YBX1, on the MDR1 promoter. Together with NPM1, associates with rRNA. Binds DNA and RNA By similarity.
The C-O-P bond 3' to the apurinic or apyrimidinic site in DNA is broken by a beta-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate.
Magnesium. Can also utilize manganese. Probably binds two magnesium or manganese ions per subunit By similarity.
NPM1 stimulates endodeoxyribonuclease activity on double-stranded DNA with AP sites, but inhibits endoribonuclease activity on single-stranded RNA containing AP sites By similarity.
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, POLB, PRDX6, PRPF19, RPLP0, TOMM20 and WDR77. Binds to CDK5 By similarity.
Nucleus. Nucleus › nucleolus By similarity. Nucleus speckle By similarity. Endoplasmic reticulum By similarity. Cytoplasm By similarity. Note: Detected in the cytoplasm of B-cells stimulated to switch. 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 By similarity. 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 By similarity.
DNA-(apurinic or apyrimidinic site) lyase, mitochondrial: Mitochondrion. Note: 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. The cleaved APEX2 is only detected in mitochondria By similarity.
The N-terminus contains the redox activity while the C-terminus exerts the DNA AP-endodeoxyribonuclease activity; both function 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 By similarity.
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 in response to MPP+/MPTP (1-methyl-4-phenylpyridinium) reduces AP-endodeoxyribonuclease activity resulting in accumulation of DNA damage and contributing to neuronal death By similarity.
Acetylated on Lys-6 and Lys-7. Acetylation is increased by the transcriptional coactivator EP300 acetyltransferase, genotoxic agents like H2O2 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 By similarity.
Cleaved at Lys-31 by granzyme A to create the mitochondrial form; leading in reduction of binding to DNA, AP endodeoxyribonuclease 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 By similarity.
Cys-69 and Cys-93 are nitrosylated in response to nitric oxide (NO) and lead to the exposure of the nuclear export signal (NES) By similarity.
Ubiquitinated by MDM2; leading to translocation to the cytoplasm and proteasomal degradation By similarity.
The specific activity of the cleaved mitochondrial endodeoxyribonuclease appeared to be about 3-fold higher than of the full-length form. Extract of mitochondria, but not of nuclei or cytosol, cleaves recombinant APEX1 to generate a mitochondrial APEX1-sized product By similarity.
Belongs to the DNA repair enzymes AP/ExoA family.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed By similarity|
|Chain||2 – 318||317||DNA-(apurinic or apyrimidinic site) lyase||PRO_0000285546|
|Chain||32 – 318||287||DNA-(apurinic or apyrimidinic site) lyase, mitochondrial||PRO_0000402808|
|Region||2 – 33||32||Necessary for interaction with YBX1, binding to RNA, association together with NPM1 to rRNA, endoribonuclease activity on abasic RNA and localization in the nucleoli By similarity|
|Region||8 – 13||6||Nuclear localization signal (NLS) By similarity|
|Region||23 – 33||11||Necessary for interaction with NPM1 and for efficient rRNA binding By similarity|
|Region||64 – 80||17||Nuclear export signal (NES) By similarity|
|Region||289 – 318||30||Mitochondrial targeting sequence (MTS) By similarity|
|Active site||171||1||By similarity|
|Active site||210||1||Proton donor/acceptor By similarity|
|Metal binding||70||1||Magnesium 1 By similarity|
|Metal binding||96||1||Magnesium 1 By similarity|
|Metal binding||210||1||Magnesium 2 By similarity|
|Metal binding||212||1||Magnesium 2 By similarity|
|Metal binding||308||1||Magnesium 1 By similarity|
|Site||31 – 32||2||Cleavage; by granzyme A By similarity|
|Site||212||1||Transition state stabilizer By similarity|
|Site||283||1||Important for catalytic activity By similarity|
|Site||309||1||Interaction with DNA substrate By similarity|
Amino acid modifications
|Modified residue||6||1||N6-acetyllysine; by EP300 By similarity|
|Modified residue||7||1||N6-acetyllysine; by EP300 By similarity|
|Modified residue||27||1||N6-acetyllysine By similarity|
|Modified residue||31||1||N6-acetyllysine By similarity|
|Modified residue||32||1||N6-acetyllysine By similarity|
|Modified residue||35||1||N6-acetyllysine By similarity|
|Modified residue||65||1||S-nitrosocysteine; alternate By similarity|
|Modified residue||93||1||S-nitrosocysteine; alternate By similarity|
|Modified residue||197||1||N6-acetyllysine By similarity|
|Modified residue||233||1||Phosphothreonine; by CDK5 By similarity|
|Modified residue||310||1||S-nitrosocysteine By similarity|
|Disulfide bond||65 ↔ 93||Alternate By similarity|
|DQ977185 Genomic DNA. Translation: ABM54218.1.|
|RefSeq||XP_003811777.1. XM_003811729.1. |
3D structure databases
|SMR||A1YFZ3. Positions 40-318. |
Protocols and materials databases
Genome annotation databases
Family and domain databases
|Gene3D||220.127.116.11. 1 hit. |
|InterPro||IPR004808. AP_endonuc_1. |
|PANTHER||PTHR22748. PTHR22748. 1 hit. |
|Pfam||PF03372. Exo_endo_phos. 1 hit. |
|SUPFAM||SSF56219. SSF56219. 1 hit. |
|TIGRFAMs||TIGR00633. xth. 1 hit. |
|PROSITE||PS00726. AP_NUCLEASE_F1_1. 1 hit. |
PS00727. AP_NUCLEASE_F1_2. 1 hit.
PS00728. AP_NUCLEASE_F1_3. 1 hit.
PS51435. AP_NUCLEASE_F1_4. 1 hit.
|Accession||Primary (citable) accession number: A1YFZ3|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families