Alternative titles; symbols
HGNC Approved Gene Symbol: APEX1
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38): 14:20,455,226-20,457,767 (from NCBI)
APEX nuclease, also called apurinic endonuclease (APE), is a DNA repair enzyme having apurinic/apyrimidinic (AP) endonuclease, 3-prime,5-prime-exonuclease, DNA 3-prime repair diesterase, and DNA 3-prime-phosphatase activities. AP sites resulting from loss of bases are the most frequent lesions occurring in vivo in cellular DNA. AP sites are known to be produced by spontaneous hydrolysis, by various chemicals and radiations, and by DNA glycosylases that remove particular abnormal bases from DNA. The resulting abasic sites can block the progress of the DNA replication apparatus and cause mutations. These sites must be corrected to restore genetic integrity.
Demple et al. (1991) cloned and analyzed cDNA encoding a major human APE. The predicted APE protein, which contained probable nuclear transport signals, was identified as a member of a family of DNA repair enzymes found in lower organisms. See also Robson and Hickson (1991) and Cheng et al. (1992). APE was identified by Xanthoudakis et al. (1992) as a reductive activator of c-Fos (164810) and c-Jun (165160) transcription factors. Okazaki et al. (1994) identified APE as a repressor of the parathyroid hormone gene (PTH; 168450) that binds to the negative Ca(2+)-response elements (nCaREs) in the PTH promoter.
By Northern hybridization experiments, Akiyama et al. (1994) showed that the APEX gene is expressed ubiquitously in human cells.
Izumi et al. (1996) analyzed the activity of the APE1 promoter by transient expression of a luciferase reporter gene in human, HeLa, and TK6 cells. Two nCaRE-like sequences were identified in the promoter segments responsible for inhibiting reporter gene expression. Competitive electrophoretic mobility shift assay with HeLa nuclear extract indicated that the nCaRE sequences of the APE1 and PTH genes are recognized by the APE1 polypeptide. These results suggested that the APE1 gene may be downregulated by its own product.
By electrophoretic mobility shift assay (EMSA) analysis, Jayaraman et al. (1997) determined that the factor that they called Ref1 is a potent activator of latent p53 protein by redox-dependent and -independent means.
Chou and Cheng (2002) showed that APE1 has a DNA 3-prime,5-prime-exonuclease activity on mismatched deoxyribonucleotides at the 3-prime termini of nicked or gapped DNA molecules. The activity is more efficient at short-patch repair than long-patch repair. In addition, the exonuclease activity of nuclear APE1 can remove the anti-HIV nucleoside analogs AZT and D4T from the 3-prime terminus of a nick more efficiently than can cytosolic exonucleases. Chou and Cheng (2002) proposed that APE1 may be involved in reducing the cytotoxicity and improving the therapeutic index of anti-HIV compounds belonging to the chain terminator category.
To investigate the relevance of REF1 in the growth regulation of uterine leiomyomas (150699), Orii et al. (2002) studied expression of REF1 in the myometrium and uterine smooth muscle tumors. Using 3 antibodies against different epitopes of REF1, 2 forms of REF1 protein were detected. The abundance of the large form of REF1 was increased in leiomyoma extracts relative to myometrial tissue extracts, and the large form was dominant in cell lines derived from leiomyosarcomas. A single mRNA transcript was detected in the same samples, leading the authors to hypothesize that the differentially migrating forms are the result of posttranslational modification(s). In vitro incubation of leiomyoma tissue extract led to a shift from the large form to the small form, and this conversion was inhibited by either protease or phosphatase inhibitors. The relative abundance of the large form of REF1 correlated with proliferating cell nuclear antigen levels, suggesting a correlation with increased proliferation. The authors concluded that altered posttranslational modification of REF1 is involved in uterine smooth muscle tumorigenesis.
GZMA (140050) induces caspase-independent apoptosis in a characteristic manner, except it causes a distinctive form of DNA damage: single-stranded DNA nicking. A target of GZMA is the SET (600960) complex, including HMGB2 (163906) and ANP32A (600832). Fan et al. (2003) showed that APEX is also present in the SET complex and binds to GZMA. GZMA cleaves APEX after lys31, destroying its known oxidative repair functions. Silencing of APEX expression by RNA interference nearly doubled specific cell lysis, with enhanced DNA nicking. Mutation analysis indicated that lys31 is crucial for GZMA cleavage of APEX and GZMA-induced cell death.
Using dot blot analysis and ELISA, Wong et al. (2007) showed that human CSB (ERCC6; 609413) interacted with APE1. CSB stimulated AP site incision activity of APE1 on normal (i.e., fully paired) and bubble AP-DNA substrates, with the latter being more pronounced. The activation was ATP independent and specific for human CSB and full-length APE1. Immunoprecipitation analysis showed that CSB and APE1 were present in a common protein complex in human cell extracts, and addition of CSB to CSB-deficient whole cell extracts increased total AP site incision capacity. Moreover, human fibroblasts deficient in CSB were hypersensitive to agents that introduce base excision repair DNA substrates/intermediates.
Harrison et al. (1992) determined the sequence of the APE gene, which contains 4 small introns (ranging from 130 to 566 bp) and 5 exons, the first of which is untranslated. Consistent with the constitutive expression of AP endonuclease activity observed in other studies, the 0.5 kb of DNA sequence upstream of APE revealed only a possible CCAAT box and no other regulatory sites or a TATA box.
Akiyama et al. (1994) cloned the human APEX gene and showed that it consists of 5 exons spanning 2.64 kb and exists as a single copy in the haploid genome. The boundaries between exons and introns follow the GT/AG rule. Akiyama et al. (1995) cloned the homologous gene in the mouse and determined its complete sequence. The gene consists of 5 exons and 4 introns spanning 2.21 kb, and the boundaries between exons and introns follow the GT/AG rule. Akiyama et al. (1995) described the transcription initiation sites, translation initiation and termination sites, and the characteristics of the 5-prime flanking region.
With a primer pair based on the published sequence of the bovine cDNA used in PCR, Zhao et al. (1992) amplified a 437-bp segment from human DNA without amplifying mouse or hamster DNA in somatic cell hybrids. By this method, they assigned the APE gene to chromosome 14. Using 2 contiguous APE genomic clones as probes and in situ hybridization, they regionalized the assignment to 14q12, very near to the junction of bands q11.2 and q12. Using in situ hybridization, Robson et al. (1992) mapped the APE gene to 14q11.2-q12. Akiyama et al. (1994) confirmed this localization by FISH. Using FISH, Akiyama et al. (1995) assigned the Apex gene to mouse chromosome 14C2-D1.
Hayward et al. (1999) found a common polymorphism, D148E, of the APEX gene that had an allele frequency significantly different in sporadic amyotrophic lateral sclerosis (ALS; 105400) patients compared with controls. They concluded, however, that although it may play a small role in the etiology of ALS, it is not a 'fundamental' component in most cases.
Hadi et al. (2000) identified 7 allelic variants of the APEX gene resulting in amino acid substitutions. Functional characterization indicated that 3 of the substitutions, leu104 to arg, glu126 to asp, and arg237 to ala, reduced APEX incision activity by about 40 to 60%. A substitution at an active site aspartic acid, asp283 to gly, resulted in only about 10% repair capacity. The most common substitution, asp148 to glu, which was observed at an allele frequency of 0.38, had no impact on endonuclease and DNA binding activities, nor did a more infrequent gly306-to-ala substitution. A gly241-to-arg substitution, which was predicted to slightly stabilize helix 9, resulted in somewhat enhanced endonuclease activity relative to wildtype. Hadi et al. (2000) concluded that the 4 reduced-function variants may represent low-penetrance polymorphisms that associate with increased disease susceptibility.
Xanthoudakis et al. (1996) generated Ref1 -/- mice. Unlike the healthy heterozygotes, the homozygous deficient mice died during embryonic development following blastocyst formation, shortly after the time of implantation.
Raffoul et al. (2004) characterized Ape +/- mice. Heterozygotes were Ape haploinsufficient, with a 40 to 50% reduction in Ape mRNA, protein, and 5-prime endonuclease activity in all tissues studied. G:U mismatch base excision repair was reduced by 35% in liver and by 55% in testis, but no effect was found in brain. The changes in base excision repair activity correlated with changes in DNA polymerase-beta (174760) and AP site DNA binding.
Huamani et al. (2004) found that the spontaneous mutation frequency was elevated about 2-fold in liver and spleen of 3-month-old heterozygous Apex mutant mice compared with the frequency in wildtype littermates. The mutation frequency was additionally elevated for somatic tissues from 9-month old Apex +/- mice. Genetic instability was delayed in spermatogenic cells, but it was observed in 9-month-old Apex +/- mice compared with 9-month-old wildtype mice.
Akiyama, K., Nagao, K., Oshida, T., Tsutsui, K., Yoshida, M. C., Seki, S. Cloning, sequence analysis, and chromosomal assignment of the mouse Apex gene. Genomics 26: 63-69, 1995. [PubMed: 7782087] [Full Text: https://doi.org/10.1016/0888-7543(95)80083-x]
Akiyama, K., Seki, S., Oshida, T., Yoshida, M. C. Structure, promoter analysis and chromosomal assignment of the human APEX gene. Biochim. Biophys. Acta 1219: 15-25, 1994. [PubMed: 8086453] [Full Text: https://doi.org/10.1016/0167-4781(94)90241-0]
Cheng, X., Bunville, J., Patterson, T. A. Nucleotide sequence of a cDNA for an apurinic/apyrimidinic endonuclease from HeLa cells. Nucleic Acids Res. 20: 370 only, 1992. [PubMed: 1371347] [Full Text: https://doi.org/10.1093/nar/20.2.370]
Chou, K.-M., Cheng, Y.-C. An exonucleolytic activity of human apurinic/apyrimidinic endonuclease on 3-prime mispaired DNA. Nature 415: 655-659, 2002. [PubMed: 11832948] [Full Text: https://doi.org/10.1038/415655a]
Demple, B., Herman, T., Chen, D. S. Cloning and expression of APE, the cDNA encoding the major human apurinic endonuclease: definition of a family of DNA repair enzymes. Proc. Nat. Acad. Sci. 88: 11450-11454, 1991. [PubMed: 1722334] [Full Text: https://doi.org/10.1073/pnas.88.24.11450]
Fan, Z., Beresford, P. J., Zhang, D., Xu, Z., Novina, C. D., Yoshida, A., Pommier, Y., Lieberman, J. Cleaving the oxidative repair protein Ape I enhances cell death mediated by granzyme A. Nature Immun. 4: 145-153, 2003. [PubMed: 12524539] [Full Text: https://doi.org/10.1038/ni885]
Hadi, M. Z., Coleman, M. A., Fidelis, K., Mohrenweiser, H. W., Wilson, D. M., III. Functional characterization of Ape1 variants identified in the human population. Nucleic Acids Res. 28: 3871-3879, 2000. [PubMed: 11024165] [Full Text: https://doi.org/10.1093/nar/28.20.3871]
Harrison, L., Ascione, G., Menninger, J. C., Ward, D. C., Demple, B. Human apurinic endonuclease gene (APE): structure and genomic mapping (chromosome 14q11.2-12). Hum. Molec. Genet. 1: 677-680, 1992. [PubMed: 1284593] [Full Text: https://doi.org/10.1093/hmg/1.9.677]
Hayward, C., Colville, S., Swingler, R. J., Brock, D. J. H. Molecular genetic analysis of the APEX nuclease gene in amyotrophic lateral sclerosis. Neurology 52: 1899-1901, 1999. [PubMed: 10371543] [Full Text: https://doi.org/10.1212/wnl.52.9.1899]
Huamani, J., McMahan, C. A., Herbert, D. C., Reddick, R., McCarrey, J. R., MacInnes, M. I., Chen, D. J., Walter, C. A. Spontaneous mutagenesis is enhanced in Apex heterozygous mice. Molec. Cell. Biol. 24: 8145-8153, 2004. [PubMed: 15340075] [Full Text: https://doi.org/10.1128/MCB.24.18.8145-8153.2004]
Izumi, T., Henner, D., Mitra, S. Negative regulation of the major human AP-endonuclease, a multifunctional protein. Biochemistry 35: 14679-14683, 1996. [PubMed: 8942627] [Full Text: https://doi.org/10.1021/bi961995u]
Jayaraman, L., Murthy, K. G. K., Zhu, C., Curran, T., Xanthoudakis, S., Prives, C. Identification of redox/repair protein Ref-1 as a potent activator of p53. Genes Dev. 11: 558-570, 1997. [PubMed: 9119221] [Full Text: https://doi.org/10.1101/gad.11.5.558]
Okazaki, T., Chung, U., Nishishita, T., Ebisu, S., Usuda, S., Mishiro, S., Xanthoudakis, S., Igarashi, T., Ogata, E. A redox factor protein, ref1, is involved in negative gene regulation by extracellular calcium. J. Biol. Chem. 269: 27855-27862, 1994. [PubMed: 7961715]
Orii, A., Masutani, H., Nikaido, T., Zhai, Y.-L., Kato, K., Kariya, M., Konishi, I., Yodoi, J., Fujii, S. Altered post-translational modification of redox factor 1 protein in human uterine smooth muscle tumors. J. Clin. Endocr. Metab. 87: 3754-3759, 2002. [PubMed: 12161506] [Full Text: https://doi.org/10.1210/jcem.87.8.8734]
Raffoul, J. J., Cabelof, D. C., Nakamura, J., Meira, L. B., Friedberg, E. C., Heydari, A. R. Apurinic/apyrimidinic endonuclease (APE/REF-1) haploinsufficient mice display tissue-specific differences in DNA polymerase beta-dependent base excision repair. J. Biol. Chem. 279: 18425-18433, 2004. [PubMed: 14973123] [Full Text: https://doi.org/10.1074/jbc.M313983200]
Robson, C. N., Hickson, I. D. Isolation of cDNA clones encoding a human apurinic/apyrimidinic endonuclease that corrects DNA repair and mutagenesis defects in E. coli xth (exonuclease III) mutants. Nucleic Acids Res. 19: 5519-5523, 1991. [PubMed: 1719477] [Full Text: https://doi.org/10.1093/nar/19.20.5519]
Robson, C. N., Hochhauser, D., Craig, R., Rack, K., Buckle, V. J., Hickson, I. D. Structure of the human DNA repair gene HAP1 and its localisation to chromosome 14q11.2-12. Nucleic Acids Res. 20: 4417-4421, 1992. [PubMed: 1383925] [Full Text: https://doi.org/10.1093/nar/20.17.4417]
Wong, H.-K., Muftuoglu, M., Beck, G., Imam, S. Z., Bohr, V. A., Wilson, D. M., III. Cockayne syndrome B protein stimulates apurinic endonuclease 1 activity and protects against agents that introduce base excision repair intermediates. Nucleic Acids Res. 35: 4103-4113, 2007. [PubMed: 17567611] [Full Text: https://doi.org/10.1093/nar/gkm404]
Xanthoudakis, S., Miao, G., Wang, F., Pan, Y. C., Curran, T. Redox activation of Fos-Jun DNA binding activity is mediated by a DNA repair enzyme. EMBO J. 11: 3323-3335, 1992. [PubMed: 1380454] [Full Text: https://doi.org/10.1002/j.1460-2075.1992.tb05411.x]
Xanthoudakis, S., Smeyne, R. J., Wallace, J. D., Curran, T. The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice. Proc. Nat. Acad. Sci. 93: 8919-8923, 1996. [PubMed: 8799128] [Full Text: https://doi.org/10.1073/pnas.93.17.8919]
Zhao, B., Grandy, D. K., Hagerup, J. M., Magenis, R. E., Smith, L., Chauhan, B. C., Henner, W. D. The human gene for apurinic/apyrimidinic endonuclease (HAP1): sequence and localization to chromosome 14 band q12. Nucleic Acids Res. 20: 4097-4098, 1992. [PubMed: 1380694] [Full Text: https://doi.org/10.1093/nar/20.15.4097]