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A1YFZ3

- APEX1_PANPA

UniProt

A1YFZ3 - APEX1_PANPA

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Protein

DNA-(apurinic or apyrimidinic site) lyase

Gene
APEX1, APE, APEX, BAP1, REF1
Organism
Pan paniscus (Pygmy chimpanzee) (Bonobo)
Status
Reviewed - Annotation score: 5 out of 5 - Protein inferred from homologyi

Functioni

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.

Catalytic activityi

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.

Cofactori

Magnesium. Can also utilize manganese. Probably binds two magnesium or manganese ions per subunit By similarity.

Enzyme regulationi

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

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei31 – 322Cleavage; by granzyme A By similarity
Metal bindingi70 – 701Magnesium 1 By similarity
Metal bindingi96 – 961Magnesium 1 By similarity
Active sitei171 – 1711 By similarity
Active sitei210 – 2101Proton donor/acceptor By similarity
Metal bindingi210 – 2101Magnesium 2 By similarity
Metal bindingi212 – 2121Magnesium 2 By similarity
Sitei212 – 2121Transition state stabilizer By similarity
Sitei283 – 2831Important for catalytic activity By similarity
Metal bindingi308 – 3081Magnesium 1 By similarity
Sitei309 – 3091Interaction with DNA substrate By similarity

GO - Molecular functioni

  1. 3'-5' exonuclease activity Source: UniProtKB
  2. chromatin DNA binding Source: UniProtKB
  3. damaged DNA binding Source: UniProtKB
  4. DNA-(apurinic or apyrimidinic site) lyase activity Source: UniProtKB
  5. metal ion binding Source: UniProtKB-KW
  6. oxidoreductase activity Source: UniProtKB
  7. RNA binding Source: UniProtKB-KW
  8. site-specific endodeoxyribonuclease activity, specific for altered base Source: UniProtKB

GO - Biological processi

  1. DNA catabolic process, endonucleolytic Source: GOC
  2. DNA demethylation Source: UniProtKB
  3. DNA recombination Source: UniProtKB-KW
  4. DNA repair Source: UniProtKB
  5. nucleic acid phosphodiester bond hydrolysis Source: GOC
  6. oxidation-reduction process Source: GOC
  7. positive regulation of DNA repair Source: UniProtKB
  8. regulation of mRNA stability Source: UniProtKB
  9. regulation of transcription, DNA-templated Source: UniProtKB-KW
  10. transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Activator, Endonuclease, Exonuclease, Hydrolase, Lyase, Nuclease, Repressor

Keywords - Biological processi

DNA damage, DNA recombination, DNA repair, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding, Magnesium, Metal-binding, RNA-binding

Names & Taxonomyi

Protein namesi
Recommended 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
Cleaved into the following chain:
Gene namesi
Name:APEX1
Synonyms:APE, APEX, BAP1, REF1
OrganismiPan paniscus (Pygmy chimpanzee) (Bonobo)
Taxonomic identifieri9597 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaePan

Subcellular locationi

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 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.
Chain 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.

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB
  2. endoplasmic reticulum Source: UniProtKB-SubCell
  3. mitochondrion Source: UniProtKB
  4. nuclear speck Source: UniProtKB
  5. nucleolus Source: UniProtKB
  6. nucleoplasm Source: UniProtKB
  7. nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum, Mitochondrion, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed By similarity
Chaini2 – 318317DNA-(apurinic or apyrimidinic site) lyasePRO_0000285546Add
BLAST
Chaini32 – 318287DNA-(apurinic or apyrimidinic site) lyase, mitochondrialPRO_0000402808Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei6 – 61N6-acetyllysine; by EP300 By similarity
Modified residuei7 – 71N6-acetyllysine; by EP300 By similarity
Modified residuei27 – 271N6-acetyllysine By similarity
Modified residuei31 – 311N6-acetyllysine By similarity
Modified residuei32 – 321N6-acetyllysine By similarity
Modified residuei35 – 351N6-acetyllysine By similarity
Disulfide bondi65 ↔ 93Alternate By similarity
Modified residuei65 – 651S-nitrosocysteine; alternate By similarity
Modified residuei93 – 931S-nitrosocysteine; alternate By similarity
Modified residuei197 – 1971N6-acetyllysine By similarity
Modified residuei233 – 2331Phosphothreonine; by CDK5 By similarity
Modified residuei310 – 3101S-nitrosocysteine By similarity

Post-translational modificationi

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.

Keywords - PTMi

Acetylation, Cleavage on pair of basic residues, Disulfide bond, Phosphoprotein, S-nitrosylation, Ubl conjugation

Interactioni

Subunit structurei

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.

Structurei

3D structure databases

ProteinModelPortaliA1YFZ3.
SMRiA1YFZ3. Positions 40-318.

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni2 – 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 similarityAdd
BLAST
Regioni8 – 136Nuclear localization signal (NLS) By similarity
Regioni23 – 3311Necessary for interaction with NPM1 and for efficient rRNA binding By similarityAdd
BLAST
Regioni64 – 8017Nuclear export signal (NES) By similarityAdd
BLAST
Regioni289 – 31830Mitochondrial targeting sequence (MTS) By similarityAdd
BLAST

Domaini

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.

Sequence similaritiesi

Phylogenomic databases

HOVERGENiHBG050531.
KOiK10771.

Family and domain databases

Gene3Di3.60.10.10. 1 hit.
InterProiIPR004808. AP_endonuc_1.
IPR020847. AP_endonuclease_F1_BS.
IPR020848. AP_endonuclease_F1_CS.
IPR005135. Endo/exonuclease/phosphatase.
[Graphical view]
PANTHERiPTHR22748. PTHR22748. 1 hit.
PfamiPF03372. Exo_endo_phos. 1 hit.
[Graphical view]
SUPFAMiSSF56219. SSF56219. 1 hit.
TIGRFAMsiTIGR00633. xth. 1 hit.
PROSITEiPS00726. 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]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

A1YFZ3-1 [UniParc]FASTAAdd to Basket

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MPKRGKKGAV AEDGDELRTE PEAKKSKTAA KKNDKEAAGE GPALYEDPPD    50
QKTSPSGKPA TLKICSWNVD GLRAWIKKKG LDWVKEEAPD ILCLQETKCS 100
ENKLPAELQE LPGLSHQYWS APSDKEGYSG VGLLSRQCPL KVSYGIGEEE 150
HDQEGRVIVA EFDSFVLVTA YVPNAGRGLV RLEYRQRWDE AFRKFLKGLA 200
SRKPLVLCGD LNVAHEEIDL RNPKGNKKNA GFTPQERQGF GELLQAVPLA 250
DSFRHLYPNT PYAYTFWTYM MNARSKNVGW RLDYFLLSHS LLPALCDSKI 300
RSKALGSDHC PITLYLAL 318
Length:318
Mass (Da):35,569
Last modified:February 6, 2007 - v1
Checksum:iB943A23BF487B5D3
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
DQ977185 Genomic DNA. Translation: ABM54218.1.
RefSeqiXP_003811777.1. XM_003811729.1.
XP_003811778.1. XM_003811730.1.
XP_003811779.1. XM_003811731.1.

Genome annotation databases

GeneIDi100987860.
KEGGipps:100987860.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
DQ977185 Genomic DNA. Translation: ABM54218.1 .
RefSeqi XP_003811777.1. XM_003811729.1.
XP_003811778.1. XM_003811730.1.
XP_003811779.1. XM_003811731.1.

3D structure databases

ProteinModelPortali A1YFZ3.
SMRi A1YFZ3. Positions 40-318.
ModBasei Search...
MobiDBi Search...

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

GeneIDi 100987860.
KEGGi pps:100987860.

Organism-specific databases

CTDi 328.

Phylogenomic databases

HOVERGENi HBG050531.
KOi K10771.

Family and domain databases

Gene3Di 3.60.10.10. 1 hit.
InterProi IPR004808. AP_endonuc_1.
IPR020847. AP_endonuclease_F1_BS.
IPR020848. AP_endonuclease_F1_CS.
IPR005135. Endo/exonuclease/phosphatase.
[Graphical view ]
PANTHERi PTHR22748. PTHR22748. 1 hit.
Pfami PF03372. Exo_endo_phos. 1 hit.
[Graphical view ]
SUPFAMi SSF56219. SSF56219. 1 hit.
TIGRFAMsi TIGR00633. xth. 1 hit.
PROSITEi 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.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  1. "Positive selection in transcription factor genes on the human lineage."
    Nickel G.C., Tefft D.L., Trevarthen K., Funt J., Adams M.D.
    Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].

Entry informationi

Entry nameiAPEX1_PANPA
AccessioniPrimary (citable) accession number: A1YFZ3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 1, 2007
Last sequence update: February 6, 2007
Last modified: May 14, 2014
This is version 47 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

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 By similarity.

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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