Q9UBZ4 (APEX2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
DNA-(apurinic or apyrimidinic site) lyase 2
EC=3.1.-.-
EC=4.2.99.18

Alternative name(s):
AP endonuclease XTH2
APEX nuclease 2
APEX nuclease-like 2
Apurinic-apyrimidinic endonuclease 2
Short name=AP endonuclease 2

Gene names

Name:	APEX2
Synonyms:	APE2, APEXL2, XTH2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	518 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Function as a weak 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. Displays also double-stranded DNA 3'-5' exonuclease, 3'-phosphodiesterase activities. Shows robust 3'-5' exonuclease activity on 3'-recessed heteroduplex DNA and is able to remove mismatched nucleotides preferentially. Shows fairly strong 3'-phosphodiesterase activity involved in the removal of 3'-damaged termini formed in DNA by oxidative agents. In the nucleus functions in the PCNA-dependent BER pathway. Required for somatic hypermutation (SHM) and DNA cleavage step of class switch recombination (CSR) of immunoglobulin genes. Required for proper cell cycle progression during proliferation of peripheral lymphocytes. Ref.1 Ref.8 Ref.10
Catalytic activity	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.
Cofactor	Magnesium. Can also utilize manganese. Probably binds two magnesium or manganese ions per subunit By similarity.
Enzyme regulation	3'-5' exonuclease activity is activated by sodium and manganese. 3'-5' exonuclease and 3'-phosphodiesterase activities are stimulated in presence of PCNA.
Subunit structure	Interacts with PCNA; this interaction is triggered by reactive oxygen species and increased by misincorporation of uracil in nuclear DNA. Ref.1
Subcellular location	Nucleus. Cytoplasm. Mitochondrion Probable. Note: Together with PCNA, is redistributed in discrete nuclear foci in presence of oxidative DNA damaging agents. Ref.1 Ref.10
Tissue specificity	Highly expressed in brain and kidney. Weakly expressed in the fetal brain. Ref.1
Sequence similarities	Belongs to the DNA repair enzymes AP/ExoA family.
Biophysicochemical properties	pH dependence: Optimum pH is 6.0-8.0. Ref.8

Ontologies

Keywords
Biological process	Cell cycle DNA damage DNA recombination DNA repair
Cellular component	Cytoplasm Mitochondrion Nucleus
Coding sequence diversity	Polymorphism
Ligand	DNA-binding Magnesium Metal-binding
Molecular function	Endonuclease Exonuclease Hydrolase Lyase Nuclease
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA recombination Inferred from electronic annotation. Source: UniProtKB-KW DNA repair Inferred from electronic annotation. Source: UniProtKB-KW cell cycle Inferred from electronic annotation. Source: UniProtKB-KW nucleic acid phosphodiester bond hydrolysis Inferred from electronic annotation. Source: GOC
Cellular_component	mitochondrial inner membrane Inferred from electronic annotation. Source: Compara nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	DNA binding Inferred from electronic annotation. Source: UniProtKB-KW DNA-(apurinic or apyrimidinic site) lyase activity Inferred from electronic annotation. Source: EC endonuclease activity Inferred from electronic annotation. Source: UniProtKB-KW exonuclease activity Inferred from electronic annotation. Source: UniProtKB-KW zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 518	518	DNA-(apurinic or apyrimidinic site) lyase 2		PRO_0000200014
Regions
	Region	390 – 397	8	Required for the colocalization with PCNA in nuclear foci in presence of oxidative-induced DNA damaging agents
Sites
	Active site	156	1	By similarity
	Active site	197	1	Proton donor/acceptor By similarity
	Metal binding	8	1	Magnesium 1 By similarity
	Metal binding	48	1	Magnesium 1 By similarity
	Metal binding	197	1	Magnesium 2 By similarity
	Metal binding	199	1	Magnesium 2 By similarity
	Metal binding	303	1	Magnesium 1 By similarity
	Site	199	1	Transition state stabilizer By similarity
	Site	277	1	Important for catalytic activity By similarity
	Site	304	1	Interaction with DNA substrate By similarity
Natural variations
	Natural variant	141	1	R → C. Ref.5 Corresponds to variant rs2301416 [ dbSNP | Ensembl ].		VAR_023390
	Natural variant	141	1	R → W. Corresponds to variant rs2301416 [ dbSNP | Ensembl ].		VAR_048261
	Natural variant	269	1	H → Y Identified in a patient with mtDNA maintenance disorders. Ref.11		VAR_064033
	Natural variant	392	1	N → H Identified in a patient with mtDNA maintenance disorders. Ref.11		VAR_064034
Experimental info
	Mutagenesis	269	1	H → A: Abolishes AP endodeoxyribonuclease, 3'-5' exonuclease activity and 3'-phosphodiesterase activities.
	Mutagenesis	277	1	D → A: Abolishes AP endodeoxyribonuclease, 3'-5' exonuclease activity and 3'-phosphodiesterase activities. Ref.8
	Mutagenesis	396	1	Y → A: Reduces 3'-5' exonuclease activity in presence of PCNA. Does not abolish the 3'-5' exonuclease activity. Does only partially redistributes together with PCNA in nuclear foci in presence of oxidative-induced DNA damaging agents. Ref.10
	Mutagenesis	397	1	F → A: Reduces 3'-5' exonuclease activity in presence of PCNA. Does not abolish the 3'-5' exonuclease activity. Does only partially redistributes together with PCNA in nuclear foci in presence of oxidative-induced DNA damaging agents. Ref.10
	Sequence conflict	399	1	P → S in AAD43041. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Q9UBZ4 [UniParc]. Last modified May 1, 2000. Version 1. Checksum: 08464806153F8832	FASTA	518	57,401
	10 20 30 40 50 60 MLRVVSWNIN GIRRPLQGVA NQEPSNCAAV AVGRILDELD ADIVCLQETK VTRDALTEPL 70 80 90 100 110 120 AIVEGYNSYF SFSRNRSGYS GVATFCKDNA TPVAAEEGLS GLFATQNGDV GCYGNMDEFT 130 140 150 160 170 180 QEELRALDSE GRALLTQHKI RTWEGKEKTL TLINVYCPHA DPGRPERLVF KMRFYRLLQI 190 200 210 220 230 240 RAEALLAAGS HVIILGDLNT AHRPIDHWDA VNLECFEEDP GRKWMDSLLS NLGCQSASHV 250 260 270 280 290 300 GPFIDSYRCF QPKQEGAFTC WSAVTGARHL NYGSRLDYVL GDRTLVIDTF QASFLLPEVM 310 320 330 340 350 360 GSDHCPVGAV LSVSSVPAKQ CPPLCTRFLP EFAGTQLKIL RFLVPLEQSP VLEQSTLQHN 370 380 390 400 410 420 NQTRVQTCQN KAQVRSTRPQ PSQVGSSRGQ KNLKSYFQPS PSCPQASPDI ELPSLPLMSA 430 440 450 460 470 480 LMTPKTPEEK AVAKVVKGQA KTSEAKDEKE LRTSFWKSVL AGPLRTPLCG GHREPCVMRT 490 500 510 VKKPGPNLGR RFYMCARPRG PPTDPSSRCN FFLWSRPS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human APE2 protein is mostly localized in the nuclei and to some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen." Tsuchimoto D., Sakai Y., Sakumi K., Nishioka K., Sasaki M., Fujiwara T., Nakabeppu Y. Nucleic Acids Res. 29:2349-2360(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH PCNA, SUBCELLULAR LOCATION, TISSUE SPECIFICITY. Tissue: Leukemia.
[2]	"Putative human AP endonuclease XTH2." Luna L., Rognes T., Henriksen A.C., Bjoras M., Seeberg E. Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Lung tumor.
[3]	"cDNA cloning and characterization of human APEX nuclease-like 2 (APEXL2) protein." Akiyama K., Sarker A.H., Yao M., Tsutsui K., Seki S. Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Bone marrow.
[4]	Hadi M.Z., Erzberger J.P., Ramirez M.H., Thelen M.P., Wilson D.M. III Submitted (JAN-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Lung tumor.
[5]	NIEHS SNPs program Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT CYS-141.
[6]	"The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R. Nature 434:325-337(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung.
[8]	"Human Ape2 protein has a 3'-5' exonuclease activity that acts preferentially on mismatched base pairs." Burkovics P., Szukacsov V., Unk I., Haracska L. Nucleic Acids Res. 34:2508-2515(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF ASP-277.
[9]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[10]	"Role of PCNA-dependent stimulation of 3'-phosphodiesterase and 3'-5' exonuclease activities of human Ape2 in repair of oxidative DNA damage." Burkovics P., Hajdu I., Szukacsov V., Unk I., Haracska L. Nucleic Acids Res. 37:4247-4255(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF TYR-396 AND PHE-397.
[11]	"Identification of rare DNA variants in mitochondrial disorders with improved array-based sequencing." Wang W., Shen P., Thiyagarajan S., Lin S., Palm C., Horvath R., Klopstock T., Cutler D., Pique L., Schrijver I., Davis R.W., Mindrinos M., Speed T.P., Scharfe C. Nucleic Acids Res. 39:44-58(2011) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS TYR-269 AND HIS-392.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases
EMBL GenBank DDBJ	AB049211 mRNA. Translation: BAB13764.1. AJ011311 mRNA. Translation: CAB45242.1. AB021260 mRNA. Translation: BAA78422.1. AF119046 mRNA. Translation: AAD43041.1. AY884244 Genomic DNA. Translation: AAW56941.1. AL020991 Genomic DNA. Translation: CAI43126.1. BC002959 mRNA. Translation: AAH02959.1.
IPI	IPI00083281.
RefSeq	NP_055296.2. NM_014481.3.
UniGene	Hs.659558.
3D structure databases
ProteinModelPortal	Q9UBZ4.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9UBZ4. 7 interactions.
MINT	MINT-1439290.
STRING	9606.ENSP00000364126.
PTM databases
PhosphoSite	Q9UBZ4.
Polymorphism databases
DMDM	73921676.
Proteomic databases
PaxDb	Q9UBZ4.
PeptideAtlas	Q9UBZ4.
PRIDE	Q9UBZ4.
Protocols and materials databases
DNASU	27301.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000374987; ENSP00000364126; ENSG00000169188.
GeneID	27301.
KEGG	hsa:27301.
UCSC	uc004dtz.3. human.
Organism-specific databases
CTD	27301.
GeneCards	GC0XP055043.
HGNC	HGNC:17889. APEX2.
HPA	HPA030872.
MIM	300773. gene.
neXtProt	NX_Q9UBZ4.
PharmGKB	PA38474.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0708.
HOGENOM	HOG000231386.
HOVERGEN	HBG054715.
InParanoid	Q9UBZ4.
KO	K10772.
OMA	FIDSYRC.
OrthoDB	EOG4NS3BQ.
PhylomeDB	Q9UBZ4.
Gene expression databases
ArrayExpress	Q9UBZ4.
Bgee	Q9UBZ4.
CleanEx	HS_APEX2.
Genevestigator	Q9UBZ4.
GermOnline	ENSG00000169188. Homo sapiens.
Family and domain databases
InterPro	IPR020847. AP_endonuclease_F1_BS. IPR005135. Endo/exonuclease/phosphatase. IPR004808. ExoDNase_III. IPR010666. Znf_GRF. [Graphical view]
PANTHER	PTHR22748. PTHR22748. 1 hit.
Pfam	PF03372. Exo_endo_phos. 1 hit. PF06839. zf-GRF. 1 hit. [Graphical view]
SUPFAM	SSF56219. Exo_endo_phos. 1 hit.
TIGRFAMs	TIGR00633. xth. 1 hit.
PROSITE	PS00726. AP_NUCLEASE_F1_1. 1 hit. PS00727. AP_NUCLEASE_F1_2. False negative. PS00728. AP_NUCLEASE_F1_3. False negative. PS51435. AP_NUCLEASE_F1_4. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	27301.
NextBio	50285.
SOURCE	Search...

Entry information

Entry name

APEX2_HUMAN

Accession

Primary (citable) accession number: Q9UBZ4
Secondary accession number(s): Q9Y5X7

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 30, 2005
Last sequence update:	May 1, 2000
Last modified:	May 1, 2013
This is version 106 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.