| Structural highlights
Function
[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]
Publication Abstract from PubMed
Despite the DNA duplex being central to biological functions, many intricacies of this molecule, including the dynamic nature of mismatched base pairing, are still unknown. The unique conformations adopted by DNA mismatches can provide insight into the forces at play between nucleotides. Moreover, DNA-binding proteins apply their own individualized steric and electrochemical influences on the nucleotides that they interact with, further altering base-pairing conformations. Here, seven X-ray crystallographic structures of the human nuclease apurinic/apyrimidinic (AP) endonuclease 1 (APE1) in complex with its substrate target flanked by a 5' mismatch are reported. The structures reveal how APE1 influences the conformations of a variety of different mismatched base pairs. Purine-purine mismatches containing a guanine are stabilized by a rotation of the guanine residue about the N-glycosidic bond to utilize the Hoogsteen edge for hydrogen bonding. Interestingly, no rotation of adenine, the other purine, is observed. Mismatches involving both purine and pyrimidine bases adopt wobble conformations to accommodate the mismatch. Pyrimidine-pyrimidine mismatches also wobble; however, the smaller profile of a pyrimidine base results in a gap between the Watson-Crick faces that is reduced by a C1'-C1' compression. These results advance our understanding of mismatched base pairing and the influence of a bound protein.
Apurinic/apyrimidinic (AP) endonuclease 1 processing of AP sites with 5' mismatches.,Fairlamb MS, Whitaker AM, Freudenthal BD Acta Crystallogr D Struct Biol. 2018 Aug 1;74(Pt 8):760-768. doi:, 10.1107/S2059798318003340. Epub 2018 Jul 24. PMID:30082511[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ 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
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- ↑ 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
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- ↑ 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
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- ↑ 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
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- ↑ 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
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- ↑ 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
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- ↑ 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
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- ↑ 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
- ↑ Fairlamb MS, Whitaker AM, Freudenthal BD. Apurinic/apyrimidinic (AP) endonuclease 1 processing of AP sites with 5' mismatches. Acta Crystallogr D Struct Biol. 2018 Aug 1;74(Pt 8):760-768. doi:, 10.1107/S2059798318003340. Epub 2018 Jul 24. PMID:30082511 doi:http://dx.doi.org/10.1107/S2059798318003340
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