InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: APEX1

Summary

InnateDB Protein

IDBP-595520.3

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

APEX1

Protein Name

APEX nuclease (multifunctional DNA repair enzyme) 1

Synonyms

APE; APE1; APEN; APEX; APX; HAP1; REF1;

Species

Homo sapiens

Ensembl Protein

ENSP00000451979

InnateDB Gene

IDBG-2246 (APEX1)

Protein Structure

UniProt Annotation

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. {ECO:0000269PubMed:10023679, ECO:0000269PubMed:11118054, ECO:0000269PubMed:11452037, ECO:0000269PubMed:11809897, ECO:0000269PubMed:11832948, ECO:0000269PubMed:12524539, ECO:0000269PubMed:16617147, ECO:0000269PubMed:1719477, ECO:0000269PubMed:18179823, ECO:0000269PubMed:18439621, ECO:0000269PubMed:18579163, ECO:0000269PubMed:18809583, ECO:0000269PubMed:19188445, ECO:0000269PubMed:19401441, ECO:0000269PubMed:19934257, ECO:0000269PubMed:20699270, ECO:0000269PubMed:21496894, ECO:0000269PubMed:21762700, ECO:0000269PubMed:8355688, ECO:0000269PubMed:8621488, ECO:0000269PubMed:8932375, ECO:0000269PubMed:9108029, ECO:0000269PubMed:9207062, ECO:0000269PubMed:9560228, ECO:0000269PubMed:9804799}.

Subcellular Localization

Nucleus. Nucleus, nucleolus. Nucleus speckle. Endoplasmic reticulum. Cytoplasm. Note=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. {ECO:0000250}.DNA-(apurinic or apyrimidinic site) lyase, mitochondrial: Mitochondrion. Note=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. {ECO:0000250}.

Disease Associations

Tissue Specificity

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 88 experimentally validated interaction(s) in this database.
They are also associated with 2 interaction(s) predicted by orthology.

Experimentally validated
Total	88 [view]
Protein-Protein	83 [view]
Protein-DNA	5 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	2 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0003677	DNA binding
GO:0003684	damaged DNA binding
GO:0003713	transcription coactivator activity
GO:0003714	transcription corepressor activity
GO:0003906	DNA-(apurinic or apyrimidinic site) lyase activity
GO:0004518	nuclease activity
GO:0004519	endonuclease activity
GO:0004520	endodeoxyribonuclease activity
GO:0004523	RNA-DNA hybrid ribonuclease activity
GO:0004528	phosphodiesterase I activity
GO:0004844	uracil DNA N-glycosylase activity
GO:0005515	protein binding
GO:0008081	phosphoric diester hydrolase activity
GO:0008311	double-stranded DNA 3'-5' exodeoxyribonuclease activity
GO:0008408	3'-5' exonuclease activity
GO:0016491	oxidoreductase activity
GO:0016890	site-specific endodeoxyribonuclease activity, specific for altered base
GO:0031490	chromatin DNA binding
GO:0044822	poly(A) RNA binding
GO:0046872	metal ion binding

Biological Process

GO:0000737	DNA catabolic process, endonucleolytic
GO:0000738	DNA catabolic process, exonucleolytic
GO:0006281	DNA repair
GO:0006284	base-excision repair
GO:0006310	DNA recombination
GO:0006351	transcription, DNA-templated
GO:0006355	regulation of transcription, DNA-templated
GO:0043488	regulation of mRNA stability
GO:0045739	positive regulation of DNA repair
GO:0055114	oxidation-reduction process
GO:0080111	DNA demethylation
GO:0090305	nucleic acid phosphodiester bond hydrolysis
GO:0090502	RNA phosphodiester bond hydrolysis, endonucleolytic

Cellular Component

GO:0005634	nucleus
GO:0005654	nucleoplasm
GO:0005730	nucleolus
GO:0005737	cytoplasm
GO:0005739	mitochondrion
GO:0005783	endoplasmic reticulum
GO:0005813	centrosome
GO:0005840	ribosome
GO:0016607	nuclear speck
GO:0048471	perinuclear region of cytoplasm