[APEX1_HUMAN] Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 in 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.[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]
Evolutionary Conservation
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Publication Abstract from PubMed
Non-coding apurinic/apyrimidinic (AP) sites in DNA are continually created in cells both spontaneously and by damage-specific DNA glycosylases. The biologically critical human base excision repair enzyme APE1 cleaves the DNA sugar-phosphate backbone at a position 5' of AP sites to prime DNA repair synthesis. Here we report three co-crystal structures of human APE1 bound to abasic DNA which show that APE1 uses a rigid, pre-formed, positively charged surface to kink the DNA helix and engulf the AP-DNA strand. APE1 inserts loops into both the DNA major and minor grooves and binds a flipped-out AP site in a pocket that excludes DNA bases and racemized beta-anomer AP sites. Both the APE1 active-site geometry and a complex with cleaved AP-DNA and Mn2+ support a testable structure-based catalytic mechanism. Alanine substitutions of the residues that penetrate the DNA helix unexpectedly show that human APE1 is structurally optimized to retain the cleaved DNA product. These structural and mutational results show how APE1 probably displaces bound glycosylases and retains the nicked DNA product, suggesting that APE1 acts in vivo to coordinate the orderly transfer of unstable DNA damage intermediates between the excision and synthesis steps of DNA repair.
DNA-bound structures and mutants reveal abasic DNA binding by APE1 and DNA repair coordination [corrected],Mol CD, Izumi T, Mitra S, Tainer JA Nature. 2000 Jan 27;403(6768):451-6. PMID:10667800[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑Robson CN, Hickson ID. 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. 1991 Oct 25;19(20):5519-23. PMID:1719477
↑Fan Z, Beresford PJ, Zhang D, Xu Z, Novina CD, Yoshida A, Pommier Y, Lieberman J. Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Nat Immunol. 2003 Feb;4(2):145-53. Epub 2003 Jan 13. PMID:12524539 doi:10.1038/ni885
↑Walker LJ, Robson CN, Black E, Gillespie D, Hickson ID. Identification of residues in the human DNA repair enzyme HAP1 (Ref-1) that are essential for redox regulation of Jun DNA binding. Mol Cell Biol. 1993 Sep;13(9):5370-6. PMID:8355688
↑Chung U, Igarashi T, Nishishita T, Iwanari H, Iwamatsu A, Suwa A, Mimori T, Hata K, Ebisu S, Ogata E, Fujita T, Okazaki T. The interaction between Ku antigen and REF1 protein mediates negative gene regulation by extracellular calcium. J Biol Chem. 1996 Apr 12;271(15):8593-8. PMID:8621488
↑Rothwell DG, Hickson ID. Asparagine 212 is essential for abasic site recognition by the human DNA repair endonuclease HAP1. Nucleic Acids Res. 1996 Nov 1;24(21):4217-21. PMID:8932375
↑Hirota K, Matsui M, Iwata S, Nishiyama A, Mori K, Yodoi J. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3633-8. PMID:9108029
↑Bennett RA, Wilson DM 3rd, Wong D, Demple B. Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7166-9. PMID:9207062
↑Masuda Y, Bennett RA, Demple B. Rapid dissociation of human apurinic endonuclease (Ape1) from incised DNA induced by magnesium. J Biol Chem. 1998 Nov 13;273(46):30360-5. PMID:9804799
↑Ramana CV, Boldogh I, Izumi T, Mitra S. Activation of apurinic/apyrimidinic endonuclease in human cells by reactive oxygen species and its correlation with their adaptive response to genotoxicity of free radicals. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5061-6. PMID:9560228
↑Fritz G, Kaina B. Phosphorylation of the DNA repair protein APE/REF-1 by CKII affects redox regulation of AP-1. Oncogene. 1999 Jan 28;18(4):1033-40. PMID:10023679 doi:10.1038/sj.onc.1202394
↑Wei SJ, Botero A, Hirota K, Bradbury CM, Markovina S, Laszlo A, Spitz DR, Goswami PC, Yodoi J, Gius D. Thioredoxin nuclear translocation and interaction with redox factor-1 activates the activator protein-1 transcription factor in response to ionizing radiation. Cancer Res. 2000 Dec 1;60(23):6688-95. PMID:11118054
↑Hsieh MM, Hegde V, Kelley MR, Deutsch WA. Activation of APE/Ref-1 redox activity is mediated by reactive oxygen species and PKC phosphorylation. Nucleic Acids Res. 2001 Jul 15;29(14):3116-22. PMID:11452037
↑Chou KM, Cheng YC. An exonucleolytic activity of human apurinic/apyrimidinic endonuclease on 3' mispaired DNA. Nature. 2002 Feb 7;415(6872):655-9. PMID:11832948 doi:10.1038/415655a
↑Kuninger DT, Izumi T, Papaconstantinou J, Mitra S. Human AP-endonuclease 1 and hnRNP-L interact with a nCaRE-like repressor element in the AP-endonuclease 1 promoter. Nucleic Acids Res. 2002 Feb 1;30(3):823-9. PMID:11809897
↑Chattopadhyay R, Wiederhold L, Szczesny B, Boldogh I, Hazra TK, Izumi T, Mitra S. Identification and characterization of mitochondrial abasic (AP)-endonuclease in mammalian cells. Nucleic Acids Res. 2006 Apr 14;34(7):2067-76. Print 2006. PMID:16617147 doi:10.1093/nar/gkl177
↑Berquist BR, McNeill DR, Wilson DM 3rd. Characterization of abasic endonuclease activity of human Ape1 on alternative substrates, as well as effects of ATP and sequence context on AP site incision. J Mol Biol. 2008 May 23;379(1):17-27. doi: 10.1016/j.jmb.2008.03.053. Epub 2008, Apr 3. PMID:18439621 doi:10.1016/j.jmb.2008.03.053
↑Chattopadhyay R, Das S, Maiti AK, Boldogh I, Xie J, Hazra TK, Kohno K, Mitra S, Bhakat KK. Regulatory role of human AP-endonuclease (APE1/Ref-1) in YB-1-mediated activation of the multidrug resistance gene MDR1. Mol Cell Biol. 2008 Dec;28(23):7066-80. doi: 10.1128/MCB.00244-08. Epub 2008 Sep , 22. PMID:18809583 doi:10.1128/MCB.00244-08
↑Guo Y, Chen J, Zhao T, Fan Z. Granzyme K degrades the redox/DNA repair enzyme Ape1 to trigger oxidative stress of target cells leading to cytotoxicity. Mol Immunol. 2008 Apr;45(8):2225-35. doi: 10.1016/j.molimm.2007.11.020. Epub 2008, Jan 7. PMID:18179823 doi:10.1016/j.molimm.2007.11.020
↑Georgiadis MM, Luo M, Gaur RK, Delaplane S, Li X, Kelley MR. Evolution of the redox function in mammalian apurinic/apyrimidinic endonuclease. Mutat Res. 2008 Aug 25;643(1-2):54-63. Epub 2008 May 18. PMID:18579163 doi:10.1016/j.mrfmmm.2008.04.008
↑Vascotto C, Fantini D, Romanello M, Cesaratto L, Deganuto M, Leonardi A, Radicella JP, Kelley MR, D'Ambrosio C, Scaloni A, Quadrifoglio F, Tell G. APE1/Ref-1 interacts with NPM1 within nucleoli and plays a role in the rRNA quality control process. Mol Cell Biol. 2009 Apr;29(7):1834-54. doi: 10.1128/MCB.01337-08. Epub 2009 Feb, 2. PMID:19188445 doi:10.1128/MCB.01337-08
↑Barnes T, Kim WC, Mantha AK, Kim SE, Izumi T, Mitra S, Lee CH. Identification of Apurinic/apyrimidinic endonuclease 1 (APE1) as the endoribonuclease that cleaves c-myc mRNA. Nucleic Acids Res. 2009 Jul;37(12):3946-58. doi: 10.1093/nar/gkp275. Epub 2009, Apr 28. PMID:19401441 doi:10.1093/nar/gkp275
↑Yamamori T, DeRicco J, Naqvi A, Hoffman TA, Mattagajasingh I, Kasuno K, Jung SB, Kim CS, Irani K. SIRT1 deacetylates APE1 and regulates cellular base excision repair. Nucleic Acids Res. 2010 Jan;38(3):832-45. doi: 10.1093/nar/gkp1039. Epub 2009 Nov, 24. PMID:19934257 doi:10.1093/nar/gkp1039
↑Fantini D, Vascotto C, Marasco D, D'Ambrosio C, Romanello M, Vitagliano L, Pedone C, Poletto M, Cesaratto L, Quadrifoglio F, Scaloni A, Radicella JP, Tell G. Critical lysine residues within the overlooked N-terminal domain of human APE1 regulate its biological functions. Nucleic Acids Res. 2010 Dec;38(22):8239-56. doi: 10.1093/nar/gkq691. Epub 2010, Aug 10. PMID:20699270 doi:10.1093/nar/gkq691
↑Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011 Apr 29;145(3):423-34. doi: 10.1016/j.cell.2011.03.022. Epub 2011 Apr, 14. PMID:21496894 doi:10.1016/j.cell.2011.03.022
↑Kim WC, Berquist BR, Chohan M, Uy C, Wilson DM 3rd, Lee CH. Characterization of the endoribonuclease active site of human apurinic/apyrimidinic endonuclease 1. J Mol Biol. 2011 Sep 2;411(5):960-71. doi: 10.1016/j.jmb.2011.06.050. Epub 2011, Jul 6. PMID:21762700 doi:10.1016/j.jmb.2011.06.050
↑Mol CD, Izumi T, Mitra S, Tainer JA. DNA-bound structures and mutants reveal abasic DNA binding by APE1 and DNA repair coordination [corrected] Nature. 2000 Jan 27;403(6768):451-6. PMID:10667800 doi:https://dx.doi.org/10.1038/35000249
