Protein: DNA repair nuclease/redox regulator APEX1 (EC 3.1.11.2) (EC 3.1.21.-) (APEX nuclease) (APEN) (Apurinic-apyrimidinic endonuclease 1) (AP endonuclease 1) (APE-1) (DNA-(apurinic or apyrimidinic site) endonuclease) (Redox factor-1) (REF-1) [Cleaved into: DNA repair nuclease/redox regulator APEX1, mitochondrial] (P27695)
Organism: Homo sapiens (Human)
Function: Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 are 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.
Subcellular location: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00764}. 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}.; SUBCELLULAR LOCATION: [DNA repair nuclease/redox regulator APEX1, 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}.
Sequence: MPKRGKKGAVAEDGDELRTEPEAKKSKTAAKKNDKEAAGEGPALYEDPPDQKTSPSGKPATLKICSWNVDGLRAWIKKKGLDWVKEEAPDILCLQETKCSENKLPAELQELPGLSHQYWSAPSDKEGYSGVGLLSRQCPLKVSYGIGDEEHDQEGRVIVAEFDSFVLVTAYVPNAGRGLVRLEYRQRWDEAFRKFLKGLASRKPLVLCGDLNVAHEEIDLRNPKGNKKNAGFTPQERQGFGELLQAVPLADSFRHLYPNTPYAYTFWTYMMNARSKNVGWRLDYFLLSHSLLPALCDSKIRSKALGSDHCPITLYLAL
InterPro domains: - IPR004808: AP endonuclease 1 (family) [45-318]
- IPR005135: Endonuclease/exonuclease/phosphatase (domain) [65-309]
- IPR036691: Endonuclease/exonuclease/phosphatase superfamily (homologous_superfamily) [43-317]
- IPR020848: AP endonuclease 1, conserved site (conserved_site) [251-288]
- IPR020847: AP endonuclease 1, binding site (binding_site) [89-98]
Interaction partners: - DNA repair protein XRCC1
- DNA polymerase beta
- Flap endonuclease 1
- DNA ligase 1
- Acidic leucine-rich nuclear phosphoprotein 32 family member A
- Endonuclease III-like protein 1
- N-glycosylase/DNA lyase
- Thioredoxin
- Nucleoside diphosphate kinase A
- Adenine DNA glycosylase
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0016787 (hydrolase activity), GO:0140640 (catalytic activity, acting on a nucleic acid), GO:0005515 (protein binding), GO:0016788 (hydrolase activity, acting on ester bonds), GO:0019899 (enzyme binding), GO:0140097 (catalytic activity, acting on DNA), GO:0004518 (nuclease activity), GO:0019900 (kinase binding), GO:0003906 (DNA-(apurinic or apyrimidinic site) endonuclease activity), GO:0004536 (deoxyribonuclease activity), GO:0004527 (exonuclease activity), GO:0004529 (DNA exonuclease activity), GO:0008408 (3'-5' exonuclease activity), GO:0016895 (DNA exonuclease activity, producing 5'-phosphomonoesters), GO:0016796 (exonuclease activity, active with either ribo- or deoxyribonucleic acids and producing 5'-phosphomonoesters), GO:0008296 (3'-5'-DNA exonuclease activity)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0009987 (cellular process), GO:0048519 (negative regulation of biological process), GO:0009628 (response to abiotic stimulus), GO:0019222 (regulation of metabolic process), GO:0006807 (nitrogen compound metabolic process), GO:0071840 (cellular component organization or biogenesis), GO:0071704 (organic substance metabolic process), GO:0009056 (catabolic process), GO:0009892 (negative regulation of metabolic process), GO:0044237 (cellular metabolic process), GO:0048522 (positive regulation of cellular process), GO:0050794 (regulation of cellular process), GO:0009893 (positive regulation of metabolic process), GO:0051716 (cellular response to stimulus), GO:0006950 (response to stress), GO:0048523 (negative regulation of cellular process), GO:0044238 (primary metabolic process), GO:0051172 (negative regulation of nitrogen compound metabolic process), GO:1901564 (organonitrogen compound metabolic process), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0009314 (response to radiation), GO:0046483 (heterocycle metabolic process), GO:0044248 (cellular catabolic process), GO:0019538 (protein metabolic process), GO:0060255 (regulation of macromolecule metabolic process), GO:0006725 (cellular aromatic compound metabolic process), GO:0034641 (cellular nitrogen compound metabolic process), GO:0031324 (negative regulation of cellular metabolic process), GO:0043170 (macromolecule metabolic process), GO:1901360 (organic cyclic compound metabolic process), GO:0006139 (nucleobase-containing compound metabolic process), GO:0031325 (positive regulation of cellular metabolic process), GO:0033554 (cellular response to stress), GO:0010605 (negative regulation of macromolecule metabolic process), GO:0009889 (regulation of biosynthetic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0031323 (regulation of cellular metabolic process), GO:0016043 (cellular component organization), GO:0009890 (negative regulation of biosynthetic process), GO:0080090 (regulation of primary metabolic process), GO:1901575 (organic substance catabolic process), GO:0044260 (cellular macromolecule metabolic process), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:1901565 (organonitrogen compound catabolic process), GO:0006508 (proteolysis), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0006974 (cellular response to DNA damage stimulus), GO:0051246 (regulation of protein metabolic process), GO:0030163 (protein catabolic process), GO:0006325 (chromatin organization), GO:0010468 (regulation of gene expression), GO:0036211 (protein modification process), GO:0009057 (macromolecule catabolic process), GO:0045935 (positive regulation of nucleobase-containing compound metabolic process), GO:0051254 (positive regulation of RNA metabolic process), GO:0043412 (macromolecule modification), GO:0090304 (nucleic acid metabolic process), GO:0044265 (cellular macromolecule catabolic process), GO:0031326 (regulation of cellular biosynthetic process), GO:0051247 (positive regulation of protein metabolic process), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0006259 (DNA metabolic process), GO:0010558 (negative regulation of macromolecule biosynthetic process), GO:0031327 (negative regulation of cellular biosynthetic process), GO:0051252 (regulation of RNA metabolic process), GO:0051253 (negative regulation of RNA metabolic process), GO:0010212 (response to ionizing radiation), GO:0045934 (negative regulation of nucleobase-containing compound metabolic process), GO:0010629 (negative regulation of gene expression), GO:0031399 (regulation of protein modification process), GO:2001141 (regulation of RNA biosynthetic process), GO:0070647 (protein modification by small protein conjugation or removal), GO:0006355 (regulation of DNA-templated transcription), GO:0043632 (modification-dependent macromolecule catabolic process), GO:0006281 (DNA repair), GO:0051603 (proteolysis involved in protein catabolic process), GO:0040029 (epigenetic regulation of gene expression), GO:0006338 (chromatin remodeling), GO:0045814 (negative regulation of gene expression, epigenetic), GO:1902679 (negative regulation of RNA biosynthetic process), GO:0031401 (positive regulation of protein modification process), GO:0010498 (proteasomal protein catabolic process), GO:0006357 (regulation of transcription by RNA polymerase II), GO:0031507 (heterochromatin formation), GO:1903320 (regulation of protein modification by small protein conjugation or removal), GO:0043161 (proteasome-mediated ubiquitin-dependent protein catabolic process), GO:0045892 (negative regulation of DNA-templated transcription), GO:0070828 (heterochromatin organization), GO:1903507 (negative regulation of nucleic acid-templated transcription), GO:1903508 (positive regulation of nucleic acid-templated transcription), GO:1903506 (regulation of nucleic acid-templated transcription), GO:0032446 (protein modification by small protein conjugation), GO:0019941 (modification-dependent protein catabolic process), GO:0006302 (double-strand break repair), GO:0045944 (positive regulation of transcription by RNA polymerase II), GO:0006511 (ubiquitin-dependent protein catabolic process), GO:0000122 (negative regulation of transcription by RNA polymerase II), GO:0016567 (protein ubiquitination), GO:0031398 (positive regulation of protein ubiquitination), GO:0000209 (protein polyubiquitination)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005815 (microtubule organizing center), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0031974 (membrane-enclosed lumen), GO:0005654 (nucleoplasm), GO:0043233 (organelle lumen), GO:0043229 (intracellular organelle), GO:0043227 (membrane-bounded organelle), GO:0043228 (non-membrane-bounded organelle), GO:0005813 (centrosome), GO:0043231 (intracellular membrane-bounded organelle), GO:0070013 (intracellular organelle lumen), GO:0043232 (intracellular non-membrane-bounded organelle), GO:0005856 (cytoskeleton), GO:0031981 (nuclear lumen), GO:0005634 (nucleus), GO:0015630 (microtubule cytoskeleton)