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P23196 (APEX1_BOVIN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 131. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
DNA-(apurinic or apyrimidinic site) lyase

EC=3.1.-.-
EC=4.2.99.18
Alternative name(s):
APEX nuclease
Short name=APEN
Apurinic-apyrimidinic endonuclease 1
Short name=AP endonuclease 1
REF-1
Redox factor-1
Gene names
Name:APEX1
Synonyms:APE, APEX, BAP1, REF1
OrganismBos taurus (Bovine) [Reference proteome]
Taxonomic identifier9913 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos

Protein attributes

Sequence length318 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.4

Catalytic activity

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.

Enzyme regulation

NPM1 stimulates endodeoxyribonuclease activity on double-stranded DNA with AP sites, but inhibits endoribonuclease activity on single-stranded RNA containing AP sites By similarity.

Subunit structure

Monomer. Homodimer; disulfide-linked. Component of the SET complex, composed at least of APEX1, GZMA, SET, ANP32A, HMGB2 and NME1. 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 By similarity. Binds to CDK5 By similarity.

Subcellular location

Nucleus. Nucleusnucleolus 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. 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. Ref.4

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 By similarity. The cleaved APEX2 is only detected in mitochondria. Ref.4

Tissue specificity

The mitochondrial form is expressed in liver (at protein level). Thymus. Ref.4

Induction

By several DNA damaging agents.

Domain

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.

Post-translational modification

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.

Miscellaneous

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.

Sequence similarities

Belongs to the DNA repair enzymes AP/ExoA family.

Ontologies

Keywords
   Biological processDNA damage
DNA recombination
DNA repair
Transcription
Transcription regulation
   Cellular componentCytoplasm
Endoplasmic reticulum
Mitochondrion
Nucleus
   LigandDNA-binding
Magnesium
Metal-binding
RNA-binding
   Molecular functionActivator
Endonuclease
Exonuclease
Hydrolase
Lyase
Nuclease
Repressor
   PTMAcetylation
Cleavage on pair of basic residues
Disulfide bond
Phosphoprotein
S-nitrosylation
Ubl conjugation
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processDNA catabolic process, endonucleolytic

Inferred from sequence or structural similarity. Source: GOC

DNA demethylation

Inferred from sequence or structural similarity. Source: UniProtKB

DNA recombination

Inferred from electronic annotation. Source: UniProtKB-KW

DNA repair

Inferred from sequence or structural similarity. Source: UniProtKB

cell redox homeostasis

Inferred from sequence or structural similarity. Source: AgBase

nucleic acid phosphodiester bond hydrolysis

Inferred from sequence or structural similarity. Source: GOC

positive regulation of DNA repair

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of mRNA stability

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcentrosome

Inferred from electronic annotation. Source: Ensembl

cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

endoplasmic reticulum

Inferred from electronic annotation. Source: UniProtKB-SubCell

mitochondrion

Inferred from sequence or structural similarity. Source: UniProtKB

nuclear speck

Inferred from sequence or structural similarity. Source: UniProtKB

nucleolus

Inferred from sequence or structural similarity. Source: UniProtKB

nucleoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

perinuclear region of cytoplasm

Inferred from sequence or structural similarity. Source: AgBase

   Molecular_function3'-5' exonuclease activity

Inferred from sequence or structural similarity. Source: UniProtKB

DNA binding

Inferred from sequence or structural similarity. Source: AgBase

DNA-(apurinic or apyrimidinic site) lyase activity

Inferred from sequence or structural similarity. Source: UniProtKB

RNA binding

Inferred from electronic annotation. Source: UniProtKB-KW

chromatin DNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

damaged DNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

metal ion binding

Inferred from sequence or structural similarity. Source: AgBase

oxidoreductase activity

Inferred from sequence or structural similarity. Source: UniProtKB

phosphoric diester hydrolase activity

Inferred from sequence or structural similarity. Source: AgBase

site-specific endodeoxyribonuclease activity, specific for altered base

Inferred from sequence or structural similarity. Source: UniProtKB

transcription coactivator activity

Inferred from sequence or structural similarity. Source: AgBase

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.1 Ref.3
Chain2 – 318317DNA-(apurinic or apyrimidinic site) lyase
PRO_0000200009
Chain32 – 318287DNA-(apurinic or apyrimidinic site) lyase, mitochondrial
PRO_0000402571

Regions

Region2 – 3332Necessary 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
Region8 – 136Nuclear localization signal (NLS) By similarity
Region23 – 3311Necessary for interaction with NPM1 and for efficient rRNA binding By similarity
Region64 – 8017Nuclear export signal (NES) By similarity
Region289 – 31830Mitochondrial targeting sequence (MTS) By similarity

Sites

Active site1711 By similarity
Active site2101Proton donor/acceptor By similarity
Metal binding701Magnesium 1 By similarity
Metal binding961Magnesium 1 By similarity
Metal binding2101Magnesium 2 By similarity
Metal binding2121Magnesium 2 By similarity
Metal binding3081Magnesium 1 By similarity
Site31 – 322Cleavage; by granzyme A By similarity
Site2121Transition state stabilizer By similarity
Site2831Important for catalytic activity By similarity
Site3091Interaction with DNA substrate By similarity

Amino acid modifications

Modified residue61N6-acetyllysine; by EP300 By similarity
Modified residue71N6-acetyllysine; by EP300 By similarity
Modified residue271N6-acetyllysine By similarity
Modified residue311N6-acetyllysine By similarity
Modified residue321N6-acetyllysine By similarity
Modified residue351N6-acetyllysine By similarity
Modified residue651S-nitrosocysteine; alternate By similarity
Modified residue931S-nitrosocysteine; alternate By similarity
Modified residue1971N6-acetyllysine By similarity
Modified residue2331Phosphothreonine; by CDK5 By similarity
Modified residue3101S-nitrosocysteine By similarity
Disulfide bond65 ↔ 93Alternate By similarity

Experimental info

Sequence conflict21 – 222PE → LP AA sequence Ref.3
Sequence conflict2911V → L in AAI22611. Ref.2

Secondary structure

...................................................... 318
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P23196 [UniParc].

Last modified January 23, 2007. Version 2.
Checksum: 40C733FBA2EA738D

FASTA31835,570
        10         20         30         40         50         60 
MPKRGKKGAV VEDAEEPKTE PEAKKSKAGA KKNEKEAVGE GAVLYEDPPD QKTSPSGKSA 

        70         80         90        100        110        120 
TLKICSWNVD GLRAWIKKKG LDWVKEEAPD ILCLQETKCS ENKLPVELQE LSGLSHQYWS 

       130        140        150        160        170        180 
APSDKEGYSG VGLLSRQCPL KVSYGIGEEE HDQEGRVIVA EYDAFVLVTA YVPNAGRGLV 

       190        200        210        220        230        240 
RLEYRQRWDE AFRKFLKGLA SRKPLVLCGD LNVAHEEIDL RNPKGNKKNA GFTPQERQGF 

       250        260        270        280        290        300 
GELLQAVPLT DSFRHLYPNT AYAYTFWTYM MNARSKNVGW RLDYFLLSQS VLPALCDSKI 

       310 
RSKALGSDHC PITLYLAL 

« Hide

References

« Hide 'large scale' references
[1]"Isolation of cDNA clones encoding an enzyme from bovine cells that repairs oxidative DNA damage in vitro: homology with bacterial repair enzymes."
Robson C.N., Milne A.M., Pappin D.J.C., Hickson I.D.
Nucleic Acids Res. 19:1087-1092(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 2-19.
Tissue: Thymus.
[2]NIH - Mammalian Gene Collection (MGC) project
Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: Hereford.
Tissue: Basal ganglia.
[3]"Purification and amino-terminal amino acid sequence of an apurinic/apyrimidinic endonuclease from calf thymus."
Henner W.D., Kiker N.P., Jorgensen T.J., Munck J.-N.
Nucleic Acids Res. 15:5529-5544(1987) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 2-23.
Tissue: Thymus.
[4]"Identification and characterization of mitochondrial abasic (AP)-endonuclease in mammalian cells."
Chattopadhyay R., Wiederhold L., Szczesny B., Boldogh I., Hazra T.K., Izumi T., Mitra S.
Nucleic Acids Res. 34:2067-2076(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 34-38, FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
Tissue: Liver.
[5]"Three-dimensional structure prediction of bovine AP lyase, BAP1: prediction of interaction with DNA and alterations as a result of Arg176->Ala, Asp282->Ala, and His308->Asn mutations."
Khurshid R., Salim A., Abbasi A.
Biochem. Biophys. Res. Commun. 326:711-717(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: 3D-STRUCTURE MODELING OF 40-318.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X56685 mRNA. Translation: CAA40014.1.
BC122610 mRNA. Translation: AAI22611.1.
PIRS26830.
RefSeqNP_788782.2. NM_176609.3.
UniGeneBt.1302.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1LYRmodel-A40-318[»]
1XZRmodel-A40-318[»]
1XZSmodel-A40-318[»]
1XZTmodel-A40-318[»]
ProteinModelPortalP23196.
SMRP23196. Positions 40-318.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

STRING9913.ENSBTAP00000003559.

Proteomic databases

PaxDbP23196.
PRIDEP23196.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSBTAT00000003559; ENSBTAP00000003559; ENSBTAG00000002745.
GeneID281630.
KEGGbta:281630.

Organism-specific databases

CTD328.

Phylogenomic databases

eggNOGCOG0708.
GeneTreeENSGT00530000063540.
HOGENOMHOG000034586.
HOVERGENHBG050531.
InParanoidP23196.
KOK10771.
OrthoDBEOG7C8GJ6.
TreeFamTF315048.

Enzyme and pathway databases

BRENDA4.2.99.18. 908.

Family and domain databases

Gene3D3.60.10.10. 1 hit.
InterProIPR004808. AP_endonuc_1.
IPR020847. AP_endonuclease_F1_BS.
IPR020848. AP_endonuclease_F1_CS.
IPR005135. Endo/exonuclease/phosphatase.
[Graphical view]
PANTHERPTHR22748. PTHR22748. 1 hit.
PfamPF03372. Exo_endo_phos. 1 hit.
[Graphical view]
SUPFAMSSF56219. SSF56219. 1 hit.
TIGRFAMsTIGR00633. xth. 1 hit.
PROSITEPS00726. 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.
[Graphical view]
ProtoNetSearch...

Other

NextBio20805567.

Entry information

Entry nameAPEX1_BOVIN
AccessionPrimary (citable) accession number: P23196
Secondary accession number(s): Q0IIJ5
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1991
Last sequence update: January 23, 2007
Last modified: April 16, 2014
This is version 131 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references