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Gene Review

APEX1  -  APEX nuclease (multifunctional DNA repair...

Homo sapiens

Synonyms: AP endonuclease 1, APE, APE-1, APE1, APEN, ...
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Disease relevance of APEX1


Psychiatry related information on APEX1

  • APEN has been used in several different fields of research with small data sets and this study extends its possible use to evaluate changes in mood in certain populations such as patients with bipolar disorders [5].

High impact information on APEX1

  • A GzmA-activated DNase (GAAD) is in an ER associated complex containing pp32 and the GzmA substrates SET, HMG-2, and Ape1 [6].
  • In a base excision repair system reconstituted in vitro, the rejoining of nicked mismatched DNA depended on the presence of APE1, indicating that APE1 may increase the fidelity of base excision repair and may represent a new 3' mispaired DNA repair mechanism [7].
  • Human APE1, as well as E. coli Nfo (EndoIV) and S. cerevisae Apn1, can initiate a DNA-Glycosylase independent pathway,named NIR (for Nucleotide Incision Repair), by direct incision on the 5'-side of some damaged nucleotides, such dαA, dαT, dDHU, d5ohC, etc. The result is a 3'-OH-end, that can extended directly and a 5'-dangling nucleotide that is removed by Fen1 resulting in a long patch BER-like pathway [8],[9]
  • The exonuclease activity of APE1 can remove the anti-HIV nucleoside analogues 3'-azido-3'-deoxythymidine and 2',3'-didehydro-2', 3'-dideoxythymidine from DNA, suggesting that APE1 might have an impact on the therapeutic index of antiviral compounds in this category [7].
  • Structures resembling remarkably preserved bacterial and cyanobacterial microfossils from about 3,465-million-year-old Apex cherts of the Warrawoona Group in Western Australia currently provide the oldest morphological evidence for life on Earth and have been taken to support an early beginning for oxygen-producing photosynthesis [10].
  • Both the APE1 active-site geometry and a complex with cleaved AP-DNA and Mn2+ support a testable structure-based catalytic mechanism [11].

Chemical compound and disease context of APEX1


Biological context of APEX1


Anatomical context of APEX1

  • To answer this hypothesis, we overexpressed the Ape1/ref-1 cDNA in the GCT cell line NT2/D1 using retroviral gene transduction with the vector LAPESN [2].
  • Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation [2].
  • Caspase-3 activates AN34 in a cell-free system, although caspase-3 cannot cleave Ape1 directly in vitro [18].
  • In contrast to the three DNA glycosylases, translocation of the human major AP endonuclease (hAPE) into the mitochondria was hardly observed in COS-7 cells [19].
  • Here we report that the rate-limiting enzyme of DNA base excision repair, apurinic endonuclease-1 (Ape1), which is also known as redox factor-1 (Ref-1), binds to GzmA and is contained in the SET complex, a macromolecular complex of 270-420 kDa that is associated with the endoplasmic reticulum and is targeted by GzmA during cell-mediated death [20].

Associations of APEX1 with chemical compounds

  • Changing aspartate 283 to alanine (D283A) left 10% residual activity, contrary to a previous report, but complementation of repair-deficient bacteria by the D283A Ape1 protein was consistent with its activity in vitro [21].
  • Excision of C-4'-oxidized deoxyribose lesions from double-stranded DNA by human apurinic/apyrimidinic endonuclease (Ape1 protein) and DNA polymerase beta [22].
  • Interestingly, we have found that APE1 can also inhibit the activities of both enzymes on substrates with a tetrahydrofuran (THF) residue on the 5'-downstream primer of a nick, simulating a reduced abasic site [23].
  • These results indicate that the cellular level of APE1 may differentially affect repair efficiency for DNA strand breaks but not for uracil and AP sites in DNA [24].
  • APE1-dependent repair of DNA single-strand breaks containing 3'-end 8-oxoguanine [25].

Physical interactions of APEX1

  • The altered substrate specificity, lack of stimulation by AP-endonuclease 1 (APE1) and anomalous DNA binding conformation of S326C OGG1 may contribute to its linkage to cancer incidence [26].
  • Human AP-endonuclease 1 and hnRNP-L interact with a nCaRE-like repressor element in the AP-endonuclease 1 promoter [27].
  • Stimulation of BER by p53 is correlated with its ability to interact directly both with the AP endonuclease (APE) and with DNA polymerase beta (pol beta) [28].
  • Ape1/ref-1 has also been implicated in the activation of bioreductive drugs which require reduction in order to be active and has been shown to interact with a subunit of the Ku antigen to act as a negative regulator of the parathyroid hormone promoter, as well as part of the HREBP transcription factor complex [29].
  • Small interfering RNA-mediated silencing of APE-1/Ref-1 inhibited basal and H. pylori-induced AP-1 and NF-kappaB DNA-binding activity without affecting the nuclear translocation of these transcription factors and also reduced H. pylori-induced IL-8 mRNA and protein [30].
  • APE1/Ref-1 decrease correlated with decreased DNA-binding activity of NF-kappaB mediated by soy isoflavones and radiation, thus promoting cell killing [31].

Enzymatic interactions of APEX1

  • Optimal reaction conditions for the 3 -5 exonuclease hydrolysis reaction catalyzed by APE1 in vitro have been established, and conditions when photoreactive residues are not removed by APE1 have been chosen [32].
  • 8-Oxoguanine (8-oxoG), a major ROS product in the genome, is excised by 8-oxoG-DNA glycosylase (OGG1) and the resulting abasic (AP) site is cleaved by AP-endonuclease (APE1) in the initial steps of repair [33].
  • The recent observation that Ape1-cleaved dL sites can covalently trap DNA polymerase beta during the abasic excision process suggests that efficient incision of dL by Ape1 may potentiate further problems in DNA repair [34].
  • Here we report that APE1, the major apurinic/apyrimidinic endonuclease in human cells, is the damage-specific endonuclease involved in alternative nucleotide incision repair (NIR) pathway. We show that Ape1 incises DNA containing 5,6-dihydro-2´-deoxyuridine (DHU), 5,6-dihydrothymidine (DHT), 5-hydroxy-2´-deoxyuridine (5ohU), 5-hydroxycytosine and alpha-2´-deoxynucleotides (αA, αT, αC) adducts, generating 3´-hydroxyl and 5´-phosphate termini [35] [8].

Regulatory relationships of APEX1

  • Furthermore, APE1 was able to enhance overall product formation in reconstitution of BER steps involving FEN1 cleavage followed by ligation [23].
  • Furthermore, neither APE1 activity nor its ability to stimulate long patch BER is significantly affected by p21 in vitro [36].
  • The glycosylase activity of S326C OGG1 was not significantly stimulated by the presence of AP-endonuclease [26].
  • Moreover, RPA inactivates Ape1 incision activity at an AP site within the ss region of a fork duplex, but not a transcription-like bubble intermediate [37].
  • Polymerase beta-mediated excision of 5'-terminal OAS was stimulated by Ape1 as it is for unmodified abasic sites [22].

Other interactions of APEX1


Analytical, diagnostic and therapeutic context of APEX1


  1. Polymorphisms in the DNA base excision repair genes APEX1 and XRCC1 and lung cancer risk in Xuan Wei, China. Shen, M., Berndt, S.I., Rothman, N., Mumford, J.L., He, X., Yeager, M., Welch, R., Chanock, S., Keohavong, P., Donahue, M., Zheng, T., Caporaso, N., Lan, Q. Anticancer Res. (2005) [Pubmed]
  2. Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation. Robertson, K.A., Bullock, H.A., Xu, Y., Tritt, R., Zimmerman, E., Ulbright, T.M., Foster, R.S., Einhorn, L.H., Kelley, M.R. Cancer Res. (2001) [Pubmed]
  3. Detection of oxidative clustered DNA lesions in X-irradiated mouse skin tissues and human MCF-7 breast cancer cells. Gollapalle, E., Wang, R., Adetolu, R., Tsao, D., Francisco, D., Sigounas, G., Georgakilas, A.G. Radiat. Res. (2007) [Pubmed]
  4. Elevated and altered expression of the multifunctional DNA base excision repair and redox enzyme Ape1/ref-1 in prostate cancer. Kelley, M.R., Cheng, L., Foster, R., Tritt, R., Jiang, J., Broshears, J., Koch, M. Clin. Cancer Res. (2001) [Pubmed]
  5. Approximate entropy of symptoms of mood: an effective technique to quantify regularity of mood. Yeragani, V.K., Pohl, R., Mallavarapu, M., Balon, R. Bipolar disorders. (2003) [Pubmed]
  6. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Fan, Z., Beresford, P.J., Oh, D.Y., Zhang, D., Lieberman, J. Cell (2003) [Pubmed]
  7. An exonucleolytic activity of human apurinic/apyrimidinic endonuclease on 3' mispaired DNA. Chou, K.M., Cheng, Y.C. Nature (2002) [Pubmed]
  8. The major human AP endonuclease (Ape1) is involved in the nucleotide incision repair pathway. Gros, L., Ishchenko, A.A., Ide, H., Elder, R.H., Saparbaev, M.K. Nucleic. Acids. Res. (2004) [Pubmed]
  9. Alternative nucleotide incision repair pathway for oxidative DNA damage. Ischenko, A.A., Saparbaev, M.K. Nature. (2002) [Pubmed]
  10. Questioning the evidence for Earth's oldest fossils. Brasier, M.D., Green, O.R., Jephcoat, A.P., Kleppe, A.K., Van Kranendonk, M.J., Lindsay, J.F., Steele, A., Grassineau, N.V. Nature (2002) [Pubmed]
  11. DNA-bound structures and mutants reveal abasic DNA binding by APE1 and DNA repair coordination [corrected]. Mol, C.D., Izumi, T., Mitra, S., Tainer, J.A. Nature (2000) [Pubmed]
  12. Cloning and expression of APE, the cDNA encoding the major human apurinic endonuclease: definition of a family of DNA repair enzymes. Demple, B., Herman, T., Chen, D.S. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  13. Mutations in the alpha8 loop of human APE1 alter binding and cleavage of DNA containing an abasic site. Shen, J.C., Loeb, L.A. J. Biol. Chem. (2003) [Pubmed]
  14. Impaired DNA repair via the base-excision repair pathway after focal ischemic brain injury: a protein phosphorylation-dependent mechanism reversed by hypothermic neuroprotection. Luo, Y., Ji, X., Ling, F., Li, W., Zhang, F., Cao, G., Chen, J. Front. Biosci. (2007) [Pubmed]
  15. Expression levels of the DNA repair enzyme HAP1 do not correlate with the radiosensitivities of human or HAP1-transfected rat cell lines. Herring, C.J., Deans, B., Elder, R.H., Rafferty, J.A., MacKinnon, J., Barzilay, G., Hickson, I.D., Hendry, J.H., Margison, G.P. Br. J. Cancer (1999) [Pubmed]
  16. The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation. Hofseth, L.J., Khan, M.A., Ambrose, M., Nikolayeva, O., Xu-Welliver, M., Kartalou, M., Hussain, S.P., Roth, R.B., Zhou, X., Mechanic, L.E., Zurer, I., Rotter, V., Samson, L.D., Harris, C.C. J. Clin. Invest. (2003) [Pubmed]
  17. XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein-protein interactions. Vidal, A.E., Boiteux, S., Hickson, I.D., Radicella, J.P. EMBO J. (2001) [Pubmed]
  18. Human apurinic/apyrimidinic endonuclease (Ape1) and its N-terminal truncated form (AN34) are involved in DNA fragmentation during apoptosis. Yoshida, A., Urasaki, Y., Waltham, M., Bergman, A.C., Pourquier, P., Rothwell, D.G., Inuzuka, M., Weinstein, J.N., Ueda, T., Appella, E., Hickson, I.D., Pommier, Y. J. Biol. Chem. (2003) [Pubmed]
  19. Mitochondrial targeting of human DNA glycosylases for repair of oxidative DNA damage. Takao, M., Aburatani, H., Kobayashi, K., Yasui, A. Nucleic Acids Res. (1998) [Pubmed]
  20. Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Fan, Z., Beresford, P.J., Zhang, D., Xu, Z., Novina, C.D., Yoshida, A., Pommier, Y., Lieberman, J. Nat. Immunol. (2003) [Pubmed]
  21. Dynamics of the interaction of human apurinic endonuclease (Ape1) with its substrate and product. Masuda, Y., Bennett, R.A., Demple, B. J. Biol. Chem. (1998) [Pubmed]
  22. Excision of C-4'-oxidized deoxyribose lesions from double-stranded DNA by human apurinic/apyrimidinic endonuclease (Ape1 protein) and DNA polymerase beta. Xu, Y.J., Kim, E.Y., Demple, B. J. Biol. Chem. (1998) [Pubmed]
  23. AP endonuclease 1 coordinates flap endonuclease 1 and DNA ligase I activity in long patch base excision repair. Ranalli, T.A., Tom, S., Bambara, R.A. J. Biol. Chem. (2002) [Pubmed]
  24. Requirement for human AP endonuclease 1 for repair of 3'-blocking damage at DNA single-strand breaks induced by reactive oxygen species. Izumi, T., Hazra, T.K., Boldogh, I., Tomkinson, A.E., Park, M.S., Ikeda, S., Mitra, S. Carcinogenesis (2000) [Pubmed]
  25. APE1-dependent repair of DNA single-strand breaks containing 3'-end 8-oxoguanine. Parsons, J.L., Dianova, I.I., Dianov, G.L. Nucleic Acids Res. (2005) [Pubmed]
  26. Dimerization and opposite base-dependent catalytic impairment of polymorphic S326C OGG1 glycosylase. Hill, J.W., Evans, M.K. Nucleic Acids Res. (2006) [Pubmed]
  27. Human AP-endonuclease 1 and hnRNP-L interact with a nCaRE-like repressor element in the AP-endonuclease 1 promoter. Kuninger, D.T., Izumi, T., Papaconstantinou, J., Mitra, S. Nucleic Acids Res. (2002) [Pubmed]
  28. A role for p53 in base excision repair. Zhou, J., Ahn, J., Wilson, S.H., Prives, C. EMBO J. (2001) [Pubmed]
  29. Going APE over ref-1. Evans, A.R., Limp-Foster, M., Kelley, M.R. Mutat. Res. (2000) [Pubmed]
  30. Interleukin-8 Induction by Helicobacter pylori in Gastric Epithelial Cells is Dependent on Apurinic/Apyrimidinic Endonuclease-1/Redox Factor-1. O'hara, A.M., Bhattacharyya, A., Mifflin, R.C., Smith, M.F., Ryan, K.A., Scott, K.G., Naganuma, M., Casola, A., Izumi, T., Mitra, S., Ernst, P.B., Crowe, S.E. J. Immunol. (2006) [Pubmed]
  31. Down-regulation of apurinic/apyrimidinic endonuclease 1/redox factor-1 expression by soy isoflavones enhances prostate cancer radiotherapy in vitro and in vivo. Raffoul, J.J., Banerjee, S., Singh-Gupta, V., Knoll, Z.E., Fite, A., Zhang, H., Abrams, J., Sarkar, F.H., Hillman, G.G. Cancer Res. (2007) [Pubmed]
  32. 3 -5 exonuclease activity of human apurinic/apyrimidinic endonuclease 1 towards DNAs containing dNMP and their modified analogs at the 3 end of single strand DNA break. Dyrkheeva, N.S., Khodyreva, S.N., Sukhanova, M.V., Safronov, I.V., Dezhurov, S.V., Lavrik, O.I. Biochemistry Mosc. (2006) [Pubmed]
  33. Age-dependent modulation of DNA repair enzymes by covalent modification and subcellular distribution. Szczesny, B., Bhakat, K.K., Mitra, S., Boldogh, I. Mech. Ageing Dev. (2004) [Pubmed]
  34. Action of human apurinic endonuclease (Ape1) on C1'-oxidized deoxyribose damage in DNA. Xu, Y.J., DeMott, M.S., Hwang, J.T., Greenberg, M.M., Demple, B. DNA Repair (Amst.) (2003) [Pubmed]
  35. Major oxidative products of cytosine are substrates for the nucleotide incision repair pathway. Daviet, S., Couvé-Privat, S., Gros, L., Shinozuka, K., Ide, H., Saparbaev, M., Ishchenko, A.A. DNA. Repair. (Amst). (2007) [Pubmed]
  36. Regulatory roles of p21 and apurinic/apyrimidinic endonuclease 1 in base excision repair. Tom, S., Ranalli, T.A., Podust, V.N., Bambara, R.A. J. Biol. Chem. (2001) [Pubmed]
  37. Nucleotide sequence and DNA secondary structure, as well as replication protein A, modulate the single-stranded abasic endonuclease activity of APE1. Fan, J., Matsumoto, Y., Wilson, D.M. J. Biol. Chem. (2006) [Pubmed]
  38. Role of XRCC1 in the coordination and stimulation of oxidative DNA damage repair initiated by the DNA glycosylase hOGG1. Marsin, S., Vidal, A.E., Sossou, M., Ménissier-de Murcia, J., Le Page, F., Boiteux, S., de Murcia, G., Radicella, J.P. J. Biol. Chem. (2003) [Pubmed]
  39. Substrate specificity of human endonuclease III (hNTH1). Effect of human APE1 on hNTH1 activity. Marenstein, D.R., Chan, M.K., Altamirano, A., Basu, A.K., Boorstein, R.J., Cunningham, R.P., Teebor, G.W. J. Biol. Chem. (2003) [Pubmed]
  40. Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair. Dianova, I.I., Bohr, V.A., Dianov, G.L. Biochemistry (2001) [Pubmed]
  41. Expression of the oxidative base excision repair enzymes is not induced in TK6 human lymphoblastoid cells after low doses of ionizing radiation. Inoue, M., Shen, G.P., Chaudhry, M.A., Galick, H., Blaisdell, J.O., Wallace, S.S. Radiat. Res. (2004) [Pubmed]
  42. Transfection of a human gene for the repair of X-ray- and EMS-induced DNA damage. Spiro, I.J., Barrows, L.R., Kennedy, K.A., Ling, C.C. Radiat. Res. (1986) [Pubmed]
  43. Helicobacter pylori and H2O2 increase AP endonuclease-1/redox factor-1 expression in human gastric epithelial cells. Ding, S.Z., O'Hara, A.M., Denning, T.L., Dirden-Kramer, B., Mifflin, R.C., Reyes, V.E., Ryan, K.A., Elliott, S.N., Izumi, T., Boldogh, I., Mitra, S., Ernst, P.B., Crowe, S.E. Gastroenterology (2004) [Pubmed]
  44. Two essential but distinct functions of the mammalian abasic endonuclease. Izumi, T., Brown, D.B., Naidu, C.V., Bhakat, K.K., Macinnes, M.A., Saito, H., Chen, D.J., Mitra, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
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