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Category Symbol Source: HGNC EntrezGene Ensembl GeneCards RNA genes CroW21

GIFtS
-

APEX1 Gene

protein-coding GIFtS: 69
GCID: GC14P020924

APEX nuclease (multifunctional DNA repair enzyme) 1

(Previous name: APEX nuclease (multifunctional DNA repair enzyme) )
(Previous symbol: APEX)

Explore 105 diseases affiliated with
APEX1 via

MalaCards

our new
Human Malady Compendium

(According to ¹HGNC, ²Entrez Gene,
³UniProtKB/Swiss-Prot, ⁴UniProtKB/TrEMBL, ⁵OMIM, ⁶GeneLoc, ⁷Ensembl, ⁸DME, ⁹miRBase, and/or ¹⁰fRNAdb)
About This Section

Aliases
APEX Nuclease (Multifunctional DNA Repair Enzyme) 1¹ ²		EC 4.2.99.18³ ⁸
APE¹ ² ³ ⁵		APEX Nuclease (Multifunctional DNA Repair Enzyme)¹
APEX¹ ² ³ ⁵		AP Endonuclease Class I²
APEN¹ ² ³		AP Lyase²
APX¹ ² ³		Apurinic/Apyrimidinic (Abasic) Endonuclease²
HAP1¹ ² ³		Deoxyribonuclease (Apurinic Or Apyrimidinic)²
REF1¹ ² ³		DNA-(Apurinic Or Apyrimidinic Site) Lyase²
APE-1¹ ³		Protein REF-1²
REF-1¹ ³		EC 3.1.-.-³
Apurinic-Apyrimidinic Endonuclease 1² ³		AP Endonuclease 1³
Redox Factor-1² ³		APEX Nuclease³
APE1² ³

External Ids:	HGNC: 587¹	Entrez Gene: 328²	Ensembl: ENSG00000100823⁷	OMIM: 107748⁵	UniProtKB: P27695³

Export aliases for APEX1 gene to outside databases

Previous GC identifers: GC14P018294 GC14P014710 GC14P018913 GC14P019993 GC14P001044

(According to Entrez Gene, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
About This Section

Entrez Gene summary for APEX1:

Apurinic/apyrimidinic (AP) sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or

by DNA glycosylases that remove specific abnormal bases. AP sites are pre-mutagenic lesions that can prevent normal

DNA replication so the cell contains systems to identify and repair such sites. Class II AP endonucleases cleave the

phosphodiester backbone 5' to the AP site. This gene encodes the major AP endonuclease in human cells. Splice variants

have been found for this gene; all encode the same protein. (provided by RefSeq, Jul 2008)

UniProtKB/Swiss-Prot: APEX1_HUMAN, P27695

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

Gene Wiki entry for APEX1

(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 69), Regulatory elements and Epigenetics data according to QIAGEN, SABiosciences, and/or SwitchGear Genomics)
About This Section

RefSeq DNA sequence:

NC_000014.8 NC_018925.1 NT_026437.12

Regulatory elements:

SABiosciences Regulatory transcription factor binding sites in the APEX1 gene promoter:
GR AP-1 STAT3 GR-alpha
Other transcription factors

SwitchGear Promoter luciferase reporter plasmids (see all 2): APEX1 promoter sequence

Search SABiosciences Chromatin IP Primers for APEX1

Epigenetics:

QIAGEN PyroMark CpG Assay predesigned Pyrosequencing DNA Methylation assays in human, mouse, rat APEX1

Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track

Entrez Gene cytogenetic band: 14q11.2 Ensembl cytogenetic band: 14q11.2 HGNC cytogenetic band: 14q11.2

APEX1 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
APEX1 gene location

GeneLoc information about chromosome 14 GeneLoc Exon Structure

GeneLoc location for GC14P020924: view genomic region (about GC identifiers)

Start:	20,923,290 bp from pter	End:	20,925,927 bp from pter
Size:	2,638 bases	Orientation:	plus strand

(According to ¹UniProtKB, HORDE, neXtProt, Ensembl, and/or Reactome, Modification sites according to ²PhosphoSitePlus, Specific Peptides from DME, Protein expression images according to data from SPIRE MOPED and PaxDb, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, and/or Uscn,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, and/or Uscn, Ontologies according to Gene Ontology Consortium 01 Mar 2013 and Entrez Gene, Antibodies by EMD Millipore, R&D Systems, GenScript, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, Abcam, and/or Uscn)
About This Section

UniProtKB/Swiss-Prot: APEX1_HUMAN, P27695 (See protein sequence)

Recommended Name: DNA-(apurinic or apyrimidinic site) lyase

Size: 318 amino acids; 35555 Da

Cofactor: Magnesium. Can also utilize manganese. Probably binds two magnesium or manganese ions per subunit

Subunit: 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. Binds to CDK5 (By similarity)

Subcellular location: 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

Subcellular location: 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

Miscellaneous: 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

6/12 PDB 3D structures from and Proteopedia for APEX1 (see all 12):

1BIX (3D)

1CQG (3D)

1CQH (3D)

1DE8 (3D)

1DE9 (3D)

1DEW (3D)

Secondary accessions: Q969L5 Q99775

Explore the universe of human proteins at neXtProt for APEX1: NX_P27695

Post-translational modifications:

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 reduces AP-endodeoxyribonuclease activity resulting

in accumulation of DNA damage and contributing to neuronal death¹

Acetylated on Lys-6 and Lys-7. Acetylation is increased by the transcriptional coactivator EP300 acetyltransferase,

genotoxic agents like H(2)O(2) 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 SIRT1¹

Cleaved at Lys-31 by granzyme A to create the mitochondrial form; leading in reduction of binding to DNA, AP

endodeoxynuclease 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 stress¹

Cys-65 and Cys-93 are nitrosylated in response to nitric oxide (NO) and lead to the exposure of the nuclear export

signal (NES)¹

Ubiquitinated by MDM2; leading to translocation to the cytoplasm and proteasomal degradation¹

View modification sites using PhosphoSitePlus²

View neXtProt modification sites for NX_P27695

4/6 DME Specific Peptides for APEX1 (P27695) (see all 6)

NVGWRLDY

AYTFWTYM

LKICSWNV

DSFRHLYPNT

APEX1 Protein expression data from MOPED and PaxDb: About this image

REFSEQ proteins (4 alternative transcripts):

NP_001231178.1 NP_001632.2 NP_542379.1 NP_542380.1

ENSEMBL proteins:

ENSP00000451979 ENSP00000216714 ENSP00000451327 ENSP00000452137 ENSP00000381111

ENSP00000450604 ENSP00000452304 ENSP00000452460 ENSP00000451491 ENSP00000451170

ENSP00000452212 ENSP00000451060 ENSP00000452418 ENSP00000416414

Reactome Protein details: P27695
Human Recombinant Protein Products for APEX1:

	Browse Purified and Recombinant Proteins at EMD Millipore
	Browse R&D Systems for human recombinant proteins
	Enzo Life Sciences proteins for APEX1
	OriGene Purified Proteins (see all 2): APEX1 OriGene Protein Over-expression Lysate (see all 4): APEX1 OriGene Custom Protein Services for APEX1
	GenScript Custom Purified and Recombinant Proteins Services for APEX1
	Novus Biologicals APEX1 Proteins Novus Biologicals APEX1 Lysates
	Browse Sino Biological Recombinant Proteins
	ProSpec Recombinant Protein for APEX1
	Uscn Proteins for APEX1

Gene Ontology (GO): 5/12 cellular component terms (GO ID links to tree view) (see all 12): About this table

GO ID	Qualified GO term	Evidence	PubMed IDs
GO:0005622	intracellular	--	--
GO:0005634	nucleus	IDA	--
GO:0005654	nucleoplasm	TAS	--
GO:0005667	transcription factor complex	IEA	--
GO:0005730	nucleolus	IDA	17148573

APEX1 for ontologies About GeneDecksing

APEX1 Antibody Products:

	Browse EMD Millipore's Extensive Line of Mono- and Polyclonal Antibodies
	R&D Systems Antibodies for APEX1 (APE)
	Cell Signaling Technology (CST) Antibodies for APEX1 (APE1)
	OriGene Antibodies (see all 10): APEX1 OriGene Custom Antibody Services for APEX1
	GenScript Superior Antibodies for APEX1
	Novus Biologicals APEX1 Antibodies
	Abcam antibodies for APEX1
	Uscn Antibodies for APEX1
	ThermoFisher Antibody for APEX1

Assay Products for APEX1:

	Browse Kits and Assays available from EMD Millipore
	OriGene Custom Immunoassay Development Browse OriGene Fluorogenic Cell Assay Kits
	R&D Systems ELISAs for APEX1 (APE)
	GenScript Custom Assay Services for APEX1
	Browse Enzo Life Sciences for kits & assays
	Uscn ELISAs and CLIAs for APEX1

(According to InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
About This Section

APEX1 for domains About GeneDecksing

4 InterPro domains/families:

IPR020848 AP_endonuclease_F1_CS

IPR020847 AP_endonuclease_F1_BS

IPR005135 Endo/exonuclease/phosphatase

IPR004808 ExoDNase_III

Graphical View of Domain Structure for InterPro Entry P27695

ProtoNet protein and cluster: P27695

1 Blocks protein family: IPB000097 AP endonuclease

UniProtKB/Swiss-Prot: APEX1_HUMAN, P27695

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

Similarity: Belongs to the DNA repair enzymes AP/ExoA family

(According to ¹UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or ²DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013, inGenious Targeting Laboratory,
bound targets from SABiosciences, miRNA Gene Targets from miRTarBase, shRNA from OriGene, Sirion Biotech, RNAi from EMD Millipore, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, Gene Editing from DNA2.0, Sirion Biotech, Clones from EMD Millipore, OriGene, SwitchGear Genomics, GenScript, Sino Biological, DNA2.0, and Vector BioLabs, Cell Lines from GenScript, LifeMap BioReagents, Sirion Biotech, In Situ Hybridization Assays from Advanced Cell Diagnostics, Ontologies according to Gene Ontology Consortium 01 Mar 2013 via Entrez Gene.)
About This Section

Molecular Function:

UniProtKB/Swiss-Prot Summary: APEX1_HUMAN, P27695