UniProt Accession

 APEX1_HUMAN; P27695; Q969L5; Q99775 

Genbank Protein ID

 X59764; M80261; D90373; S43127; M81955; M92444; X66133; D13370; U79268; BT007236; AF488551; AL355075; BC002338; BC004979; BC008145; BC019291; M99703 

Genbank Nucleotide ID

 CAA42437.1; AAA58371.1; BAA14381.1; AAB22977.1; AAA58372.1; AAA58629.1; CAA46925.1; BAA02633.1; AAB50212.1; AAP35900.1; AAL86909.1; AAH02338.1; AAH04979.1; AAH08145.1; AAH19291.1; AAA58373.1 

Protein Name

 DNA-(apurinic or apyrimidinic site) lyase 

Protein Synonyms/Alias

 APEX nuclease; APEN; Apurinic-apyrimidinic endonuclease 1; AP endonuclease 1; APE-1; REF-1; Redox factor-1; DNA-(apurinic or apyrimidinic site) lyase, mitochondrial 

Gene Name

 APEX1 

Gene Synonyms/Alias

 APE; APE1; APEX; APX; HAP1; REF1 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
3	*****MPKRGKKGAV	acetylation	[1]
6	**MPKRGKKGAVAED	acetylation	[1]
7	*MPKRGKKGAVAEDG	acetylation	[1]
24	LRTEPEAKKSKTAAK	ubiquitination	[2, 3]
27	EPEAKKSKTAAKKND	acetylation	[4]
31	KKSKTAAKKNDKEAA	acetylation	[4]
32	KSKTAAKKNDKEAAG	acetylation	[4]
35	TAAKKNDKEAAGEGP	acetylation	[4]
85	KKGLDWVKEEAPDIL	ubiquitination	[5]
125	YWSAPSDKEGYSGVG	ubiquitination	[2]
197	EAFRKFLKGLASRKP	acetylation	[6]
197	EAFRKFLKGLASRKP	ubiquitination	[5]
228	RNPKGNKKNAGFTPQ	ubiquitination	[5]

Reference

 [1] Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene.
 Bhakat KK, Izumi T, Yang SH, Hazra TK, Mitra S.
 EMBO J. 2003 Dec 1;22(23):6299-309. [PMID: 14633989]
 [2] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [3] Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.
 Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW.
 Nature. 2013 Apr 18;496(7445):372-6. [PMID: 23503661]
 [4] Critical lysine residues within the overlooked N-terminal domain of human APE1 regulate its biological functions.
 Fantini D, Vascotto C, Marasco D, D'Ambrosio C, Romanello M, Vitagliano L, Pedone C, Poletto M, Cesaratto L, Quadrifoglio F, Scaloni A, Radicella JP, Tell G.
 Nucleic Acids Res. 2010 Dec;38(22):8239-56. [PMID: 20699270]
 [5] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [6] Lysine acetylation targets protein complexes and co-regulates major cellular functions.
 Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M.
 Science. 2009 Aug 14;325(5942):834-40. [PMID: 19608861] 

Functional Description

 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. 

Sequence Annotation

 REGION 2 33 Necessary for interaction with YBX1,
 REGION 8 13 Nuclear localization signal (NLS).
 REGION 23 33 Necessary for interaction with NPM1 and
 REGION 64 80 Nuclear export signal (NES).
 REGION 289 318 Mitochondrial targeting sequence (MTS).
 ACT_SITE 171 171
 ACT_SITE 210 210 Proton donor/acceptor.
 METAL 70 70 Magnesium 1.
 METAL 96 96 Magnesium 1.
 METAL 210 210 Magnesium 2.
 METAL 212 212 Magnesium 2.
 METAL 308 308 Magnesium 1.
 MOD_RES 6 6 N6-acetyllysine; by EP300.
 MOD_RES 7 7 N6-acetyllysine; by EP300.
 MOD_RES 27 27 N6-acetyllysine.
 MOD_RES 31 31 N6-acetyllysine.
 MOD_RES 32 32 N6-acetyllysine.
 MOD_RES 35 35 N6-acetyllysine.
 MOD_RES 65 65 S-nitrosocysteine.
 MOD_RES 93 93 S-nitrosocysteine.
 MOD_RES 197 197 N6-acetyllysine.
 MOD_RES 233 233 Phosphothreonine; by CDK5 (By
 MOD_RES 310 310 S-nitrosocysteine.
 DISULFID 65 93 Probable.  

Keyword

 3D-structure; Acetylation; Activator; Cleavage on pair of basic residues; Complete proteome; Cytoplasm; Direct protein sequencing; Disulfide bond; DNA damage; DNA recombination; DNA repair; DNA-binding; Endonuclease; Endoplasmic reticulum; Exonuclease; Hydrolase; Lyase; Magnesium; Metal-binding; Mitochondrion; Nuclease; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Repressor; RNA-binding; S-nitrosylation; Transcription; Transcription regulation; Ubl conjugation. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 318 AA 

Protein Sequence

Gene Ontology

 GO:0005813; C:centrosome; IDA:HPA.
 GO:0005783; C:endoplasmic reticulum; TAS:UniProtKB.
 GO:0005739; C:mitochondrion; IDA:UniProtKB.
 GO:0016607; C:nuclear speck; IDA:UniProtKB.
 GO:0005730; C:nucleolus; IDA:UniProtKB.
 GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
 GO:0005840; C:ribosome; TAS:UniProtKB.
 GO:0005667; C:transcription factor complex; IEA:Compara.
 GO:0008408; F:3'-5' exonuclease activity; IDA:UniProtKB.
 GO:0031490; F:chromatin DNA binding; IDA:UniProtKB.
 GO:0003684; F:damaged DNA binding; IDA:UniProtKB.
 GO:0003906; F:DNA-(apurinic or apyrimidinic site) lyase activity; IDA:UniProtKB.
 GO:0046872; F:metal ion binding; IDA:UniProtKB.
 GO:0016491; F:oxidoreductase activity; IDA:UniProtKB.
 GO:0004528; F:phosphodiesterase I activity; TAS:UniProtKB.
 GO:0004523; F:ribonuclease H activity; TAS:UniProtKB.
 GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
 GO:0016890; F:site-specific endodeoxyribonuclease activity, specific for altered base; IDA:UniProtKB.
 GO:0003713; F:transcription coactivator activity; IDA:UniProtKB.
 GO:0003714; F:transcription corepressor activity; TAS:ProtInc.
 GO:0004844; F:uracil DNA N-glycosylase activity; TAS:ProtInc.
 GO:0007568; P:aging; IEA:Compara.
 GO:0006284; P:base-excision repair; TAS:Reactome.
 GO:0045454; P:cell redox homeostasis; IEA:Compara.
 GO:0071320; P:cellular response to cAMP; IEA:Compara.
 GO:0070301; P:cellular response to hydrogen peroxide; IEA:Compara.
 GO:0071375; P:cellular response to peptide hormone stimulus; IEA:Compara.
 GO:0080111; P:DNA demethylation; IDA:UniProtKB.
 GO:0006310; P:DNA recombination; IEA:UniProtKB-KW.
 GO:0014912; P:negative regulation of smooth muscle cell migration; IEA:Compara.
 GO:0045739; P:positive regulation of DNA repair; IDA:UniProtKB.
 GO:0043488; P:regulation of mRNA stability; IMP:UniProtKB.
 GO:0006355; P:regulation of transcription, DNA-dependent; IEA:UniProtKB-KW.
 GO:0042493; P:response to drug; IEA:Compara.
 GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW. 

Interpro

 IPR020847; AP_endonuclease_F1_BS.
 IPR020848; AP_endonuclease_F1_CS.
 IPR005135; Endo/exonuclease/phosphatase.
 IPR004808; ExoDNase_III. 

Pfam

 PF03372; Exo_endo_phos 

SMART

  

PROSITE

 PS00726; AP_NUCLEASE_F1_1
 PS00727; AP_NUCLEASE_F1_2
 PS00728; AP_NUCLEASE_F1_3
 PS51435; AP_NUCLEASE_F1_4 

PRINTS