Alternative titles; symbols
HGNC Approved Gene Symbol: APEX2
Cytogenetic location: Xp11.21 Genomic coordinates (GRCh38) : X:55,000,363-55,009,057 (from NCBI)
APEX2 is a member of the apurinic/apyrimidinic (AP) family of endonucleases (see APEX1; 107748) that initiate the repair of AP sites formed by spontaneous hydrolysis of the N-glycosylic bond, mutagen-induced base release, or damaged-base excision by a DNA repair glycosylase (Hadi et al., 2002).
By database analysis using AP endonuclease sequences from S. pombe and other organisms as query, followed by PCR of a human leukemia cDNA library, Tsuchimoto et al. (2001) cloned APEX2, which they called APE2. The deduced 518-amino acid protein has a calculated molecular mass of 59.1 kD. APEX2 contains a predicted N-terminal mitochondrial targeting sequence, a C-terminal region that shares homology with S. cerevisiae APN2/ETH1, a putative PCNA (176740)-binding motif, and a C-terminal subregion that is homologous to a tandem repeat in the C-terminal region of DNA topoisomerase III (see TOP3A; 601243) family proteins. RT-PCR detected APEX2 expression in HeLa cells, Jurkat cells, and human kidney, brain and fetal brain tissue. Tsuchimoto et al. (2001) localized APEX2 to the mitochondria by immunocytochemistry and demonstrated that the APEX2 amino acid residues 1 to 15 function as a mitochondrial targeting sequence. Immunohistochemical studies showed a partial colocalization of APEX2 and PCNA in nuclear foci in HeLa cells.
Ide et al. (2003) used the human APEX2 sequence as probe to isolate the mouse Apex2 cDNA from a mouse spleen cDNA library. Human APEX2 shares 83% amino acid identity with its mouse homolog. Northern blot analysis of mouse tissues detected strong expression in thymus, spleen, bone marrow, and kidney with lower expression in eye, lung, brain, and uterus and no expression in stomach and salivary gland.
Tsuchimoto et al. (2001) used immunoprecipitation and in vitro pull-down binding assays to detect interaction between APEX2 and PCNA. Using HAT medium and deoxyuridine supplementation, Tsuchimoto et al. (2001) showed that misincorporation of uracil in nuclear DNA increased APEX2-PCNA association in nuclear foci, and they suggested that APEX2 participates in both nuclear and mitochondrial base excision repair (BER).
Hadi et al. (2002) identified the critical catalytic residues and structural determinants influencing APEX2 enzymatic activity and demonstrated that APEX2 displayed weaker AP site-specific and 3-prime nuclease activities compared to APEX1.
Ide et al. (2003) determined that mouse Apex2 mRNA levels increased transiently and reached a maximum in the late S phase in serum-stimulated BALB/3T3 cells. They suggested that Apex2 participates in postreplicative BER.
Burkovics et al. (2006) carried out biochemical studies using purified recombinant APEX2. They showed that APEX2 exhibited weak AP endonuclease activity but displayed strong 3-5-prime exonuclease and 3-prime phosphodiesterase activities. They suggested that APEX2 plays a role in processing 3-prime-damaged termini or 3-prime-mismatched nucleotides.
Tsuchimoto et al. (2001) determined that the APEX2 gene contains 6 exons.
By genomic sequence analysis, Tsuchimoto et al. (2001) mapped the APEX2 gene to chromosome Xp11.21.
Ide et al. (2004) demonstrated that Apex2-null mice exhibited a growth retardation phenotype (80% the size of wildtype littermates) with moderate dyshematopoiesis and severe defect in lymphopoiesis. Apex2-null mice showed significant accumulation of thymocytes and mitogen-stimulated splenocytes in G2/M phase compared to wildtype, indicating that APEX2 is required for proper cell cycle progression of proliferating lymphocytes.
Burkovics, P., Szukacsov, V., Unk, I., Haracska, L. Human Ape2 protein has 3-5-prime exonuclease activity that acts preferentially on mismatched base pairs. Nucleic Acids Res. 34: 2508-2515, 2006. [PubMed: 16687656] [Full Text: https://doi.org/10.1093/nar/gkl259]
Hadi, M. Z., Ginalski, K., Nguyen, L. H., Wilson, D. M., III. Determinants in nuclease specificity of Ape1 and Ape2, human homologues of Escherichia coli exonuclease III. J. Molec. Biol. 316: 853-866, 2002. [PubMed: 11866537] [Full Text: https://doi.org/10.1006/jmbi.2001.5382]
Ide, Y., Tsuchimoto, D., Tominaga, Y., Iwamoto, Y., Nakabeppu, Y. Characterization of the genomic structure and expression of the mouse Apex2 gene. Genomics 81: 47-57, 2003. [PubMed: 12573260] [Full Text: https://doi.org/10.1016/s0888-7543(02)00009-5]
Ide, Y., Tsuchimoto, D., Tominaga, Y., Nakashima, M., Watanabe, T., Sakumi, K., Ohno, M., Nakabeppu, Y. Growth retardation and dyslymphopoiesis accompanied by G2/M arrest in APEX2-null mice. Blood 104: 4097-4103, 2004. [PubMed: 15319281] [Full Text: https://doi.org/10.1182/blood-2004-04-1476]
Tsuchimoto, D., Sakai, Y., Sakumi, K., Nishioka, K., Sasaki, M., Fujiwara, T., Nakabeppu, Y. 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. Nucleic Acids Res. 29: 2349-2360, 2001. [PubMed: 11376153] [Full Text: https://doi.org/10.1093/nar/29.11.2349]