APEX1 - DNA-(apurinic or apyrimidinic site) lyase - human protein (Function)
 
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APEX1 »  DNA-(apurinic or apyrimidinic site) lyase   [ EC 4.2.99.18EC 3.1.-.- ]
 
Protein also known as:  Apurinic-apyrimidinic endonuclease 1 (APE-1). Cleaved into:  DNA-(apurinic or apyrimidinic site) lyase, mitochondrial.
Gene name:  APEX1
Entry whose protein(s) existence is based on evidence at protein level
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GENE REF ISO

Function

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Overview 
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.  
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  • UniProtKB
GO molecular function 
3'-5' exonuclease activitydefinition[GO:0008408]  
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  • UniProtKB
Chromatin DNA bindingdefinition[GO:0031490]  
1
  • UniProtKB
Damaged DNA bindingdefinition[GO:0003684]  
1
  • UniProtKB
DNA bindingdefinition[GO:0003677]  
1
  • UniProtKB
DNA-(apurinic or apyrimidinic site) lyase activitydefinition[GO:0003906]  
2
  • UniProtKB
Double-stranded DNA 3'-5' exodeoxyribonuclease activitydefinition[GO:0008311]  
1
  • RefGenome
Endodeoxyribonuclease activitydefinition[GO:0004520]  
1
  • PINC
Endonuclease activitydefinition[GO:0004519]  
1
  • MGI
Metal ion bindingdefinition[GO:0046872]  
1
  • UniProtKB
NF-kappaB bindingdefinition[GO:0051059] silver  
1
  • Ortholog Compara
Oxidoreductase activitydefinition[GO:0016491]  
2
  • UniProtKB
Phosphodiesterase I activitydefinition[GO:0004528]  
1
  • UniProtKB
Phosphoric diester hydrolase activitydefinition[GO:0008081]  
1
  • MGI
Poly(A) RNA bindingdefinition[GO:0044822]  
1
  • UniProtKB
Protein bindingdefinition[GO:0005515]  
15
  • IntAct
  • UniProtKB
Protein complex bindingdefinition[GO:0032403] silver  
1
  • Ortholog Compara
RNA-DNA hybrid ribonuclease activitydefinition[GO:0004523]  
1
  • UniProtKB
Site-specific endodeoxyribonuclease activity, specific for altered basedefinition[GO:0016890]  
1
  • UniProtKB
Transcription coactivator activitydefinition[GO:0003713]  
1
  • UniProtKB
Transcription corepressor activitydefinition[GO:0003714]  
1
  • PINC
Uracil DNA N-glycosylase activitydefinition[GO:0004844]  
1
  • PINC
GO biological process 
Agingdefinition[GO:0007568] silver  
1
  • Ortholog Compara
Base-excision repairdefinition[GO:0006284]  
1
  • RefGenome
Cell redox homeostasisdefinition[GO:0045454] silver  
1
  • Ortholog Compara
Cellular response to cAMPdefinition[GO:0071320] silver  
1
  • Ortholog Compara
Cellular response to hydrogen peroxidedefinition[GO:0070301] silver  
1
  • Ortholog Compara
Cellular response to peptide hormone stimulusdefinition[GO:0071375] silver  
1
  • Ortholog Compara
DNA catabolic process, endonucleolyticdefinition[GO:0000737]  
4
  • GOC
  • EC 2 GO
DNA catabolic process, exonucleolyticdefinition[GO:0000738]  
1
  • RefGenome
DNA demethylationdefinition[GO:0080111]  
1
  • UniProtKB
DNA recombinationdefinition[GO:0006310]  
1
  • UniProtKB KW
DNA repairdefinition[GO:0006281]  
1
  • UniProtKB
Negative regulation of nucleic acid-templated transcriptiondefinition[GO:1903507]  
1
  • GOC
Negative regulation of smooth muscle cell migrationdefinition[GO:0014912] silver  
1
  • Ortholog Compara
Oxidation-reduction processdefinition[GO:0055114]  
2
  • GOC
Positive regulation of DNA repairdefinition[GO:0045739]  
1
  • UniProtKB
Positive regulation of G1/S transition of mitotic cell cycledefinition[GO:1900087] silver  
1
  • Ortholog Compara
Regulation of mRNA stabilitydefinition[GO:0043488]  
1
  • UniProtKB
Regulation of transcription, DNA-templateddefinition[GO:0006355]  
1
  • UniProtKB KW
Response to drugdefinition[GO:0042493] silver  
1
  • Ortholog Compara
RNA phosphodiester bond hydrolysis, endonucleolyticdefinition[GO:0090502] silver  
1
  • Ortholog Compara
Transcription, DNA-templateddefinition[GO:0006351]  
1
  • UniProtKB KW
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reaction
EC 4.2.99.18: 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.  
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  • UniProtKB
  • PROSITE-ProRule
It requires the following cofactor
 Mg(2+) : Probably binds two magnesium or manganese ions per subunit.  
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  • UniProtKB
It is regulated in the following manner
NPM1 stimulates endodeoxyribonuclease activity on double-stranded DNA with AP sites, but inhibits endoribonuclease activity on single-stranded RNA containing AP sites.  
1
  • UniProtKB
 
More information is available from:
Pathways 
According to KEGG, this protein belongs to the following pathway:
Base excision repair  hsa03410+328  
According to Reactome, this protein belongs to the following pathways:
Base-free sugar-phosphate removal via the single-nucleotide replacement pathway  REACT_1357  
Displacement of DNA glycosylase by APE1  REACT_1064  
Gap-filling DNA repair synthesis and ligation in GG-NER  REACT_1998  
Gap-filling DNA repair synthesis and ligation in TC-NER  REACT_74  
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)  REACT_228019  
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)  REACT_228145  
Processive synthesis on the C-strand of the telomere  REACT_8027  
Processive synthesis on the lagging strand  REACT_1385  
Removal of DNA patch containing abasic residue  REACT_2192  
Resolution of AP sites via the multiple-nucleotide patch replacement pathway  REACT_1128  
Resolution of D-loop structures through Holliday junction intermediates  REACT_977  
Note 
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 appeared to be about 3-fold higher than that of the full-length form.  
1
  • UniProtKB
 

Keywords

Biological process 
DNA damage  definition   [KW-0227]
DNA recombination  definition   [KW-0233]
DNA repair  definition   [KW-0234]
Transcription  definition   [KW-0804]
Transcription regulation  definition   [KW-0805]
Molecular function 
Activator  definition   [KW-0010]
Endonuclease  definition   [KW-0255]
Exonuclease  definition   [KW-0269]
Hydrolase  definition   [KW-0378]
Lyase  definition   [KW-0456]
Nuclease  definition   [KW-0540]
Repressor  definition   [KW-0678]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

GeneWiki: APEX1
GenomeRNAi: 328
PRO: PR:P27695