Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT53OI14)

• DOT Name: DNA repair nuclease/redox regulator APEX1 (APEX1)
• Synonyms: EC 3.1.11.2; EC 3.1.21.-; APEX nuclease; APEN; Apurinic-apyrimidinic endonuclease 1; AP endonuclease 1; APE-1; DNA-(apurinic or apyrimidinic site) endonuclease; REF-1; Redox factor-1
• Gene Name: APEX1
• Related Disease: Amyotrophic lateral sclerosis
• UniProt ID: APEX1_HUMAN
• PDB ID: 1BIX ; 1CQG ; 1CQH ; 1DE8 ; 1DE9 ; 1DEW ; 1E9N ; 1HD7 ; 2ISI ; 2O3H ; 3U8U ; 4IEM ; 4LND ; 4QH9 ; 4QHD ; 4QHE ; 5CFG ; 5DFF ; 5DFH ; 5DFI ; 5DFJ ; 5DG0 ; 5WN0 ; 5WN1 ; 5WN2 ; 5WN3 ; 5WN4 ; 5WN5 ; 6BOQ ; 6BOR ; 6BOS ; 6BOT ; 6BOU ; 6BOV ; 6BOW ; 6MK3 ; 6MKK ; 6MKM ; 6MKO ; 6P93 ; 6P94 ; 6W0Q ; 6W2P ; 6W3L ; 6W3N ; 6W3Q ; 6W3U ; 6W43 ; 6W4I ; 6W4T ; 7LPG ; 7LPH ; 7LPI ; 7LPJ ; 7MCR ; 7MEV ; 7SUV ; 7SVB ; 7TC2 ; 7TC3 ; 7TR7 ; 7U50
• EC Number: 3.1.11.2; 3.1.21.-
• Pfam ID: PF03372
• Sequence:
  MPKRGKKGAVAEDGDELRTEPEAKKSKTAAKKNDKEAAGEGPALYEDPPDQKTSPSGKPA
  TLKICSWNVDGLRAWIKKKGLDWVKEEAPDILCLQETKCSENKLPAELQELPGLSHQYWS
  APSDKEGYSGVGLLSRQCPLKVSYGIGDEEHDQEGRVIVAEFDSFVLVTAYVPNAGRGLV
  RLEYRQRWDEAFRKFLKGLASRKPLVLCGDLNVAHEEIDLRNPKGNKKNAGFTPQERQGF
  GELLQAVPLADSFRHLYPNTPYAYTFWTYMMNARSKNVGWRLDYFLLSHSLLPALCDSKI
  RSKALGSDHCPITLYLAL
• Function: Multifunctional protein that plays a central role in the cellular response to oxidative stress. The two major activities of APEX1 are DNA repair and redox regulation of transcriptional factors. Functions as an 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. Also incises 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 3'-5' exoribonuclease activity on mismatched deoxyribonucleotides at the 3' termini of nicked or gapped DNA molecules during short-patch BER. Possesses 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 protection from granzyme-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.
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway:
  POLB-Dependent Long Patch Base Excision Repair (R-HSA-110362)
  Resolution of AP sites via the multiple-nucleotide patch replacement pathway (R-HSA-110373)
  PCNA-Dependent Long Patch Base Excision Repair (R-HSA-5651801)
  Abasic sugar-phosphate removal via the single-nucleotide replacement pathway (R-HSA-73930)
  Resolution of Abasic Sites (AP sites) (R-HSA-73933)
  Displacement of DNA glycosylase by APEX1 (R-HSA-110357)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 13 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	DNA repair nuclease/redox regulator APEX1 (APEX1) affects the response to substance of Arsenic.	[19]
Temozolomide	DMKECZD	Approved	DNA repair nuclease/redox regulator APEX1 (APEX1) increases the response to substance of Temozolomide.	[20]
Fluorouracil	DMUM7HZ	Approved	DNA repair nuclease/redox regulator APEX1 (APEX1) increases the response to substance of Fluorouracil.	[20]
Etoposide	DMNH3PG	Approved	DNA repair nuclease/redox regulator APEX1 (APEX1) decreases the response to substance of Etoposide.	[16]
DTI-015	DMXZRW0	Approved	DNA repair nuclease/redox regulator APEX1 (APEX1) increases the response to substance of DTI-015.	[21]
Busulfan	DMXYJ9C	Approved	DNA repair nuclease/redox regulator APEX1 (APEX1) increases the response to substance of Busulfan.	[20]
Zalcitabine	DMH7MUV	Approved	DNA repair nuclease/redox regulator APEX1 (APEX1) increases the response to substance of Zalcitabine.	[21]
Floxuridine	DM04LR2	Approved	DNA repair nuclease/redox regulator APEX1 (APEX1) increases the response to substance of Floxuridine.	[20]
Thiotepa	DMIZKOP	Approved	DNA repair nuclease/redox regulator APEX1 (APEX1) increases the response to substance of Thiotepa.	[20]
Dacarbazine	DMNPZL4	Approved	DNA repair nuclease/redox regulator APEX1 (APEX1) increases the response to substance of Dacarbazine.	[20]
Streptozocin	DMOF7AT	Approved	DNA repair nuclease/redox regulator APEX1 (APEX1) increases the response to substance of Streptozocin.	[20]
Paraquat	DMR8O3X	Investigative	DNA repair nuclease/redox regulator APEX1 (APEX1) affects the response to substance of Paraquat.	[22]
Lead acetate	DML0GZ2	Investigative	DNA repair nuclease/redox regulator APEX1 (APEX1) decreases the response to substance of Lead acetate.	[23]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[8]
Triclosan	DMZUR4N	Approved	Triclosan affects the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the activity of DNA repair nuclease/redox regulator APEX1 (APEX1).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[14]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[17]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of DNA repair nuclease/redox regulator APEX1 (APEX1).	[18]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol affects the localization of DNA repair nuclease/redox regulator APEX1 (APEX1).	[6]
Hesperetin	DMKER83	Approved	Hesperetin affects the binding of DNA repair nuclease/redox regulator APEX1 (APEX1).	[12]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the acetylation of DNA repair nuclease/redox regulator APEX1 (APEX1).	[16]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Oncoprotein SET dynamically regulates cellular stress response through nucleocytoplasmic transport in breast cancer. Cell Biol Toxicol. 2023 Aug;39(4):1795-1814. doi: 10.1007/s10565-022-09784-4. Epub 2022 Dec 19.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance. Toxicol Sci. 2012 Aug;128(2):387-97. doi: 10.1093/toxsci/kfs152. Epub 2012 Apr 26.
• [9] The modulatory effect of triclosan on the reversion of the activated phenotype of LX-2 hepatic stellate cells. J Biochem Mol Toxicol. 2020 Jan;34(1):e22413. doi: 10.1002/jbt.22413. Epub 2019 Nov 12.
• [10] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [11] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [12] Various concentrations of hesperetin induce different types of programmed cell death in human breast cancerous and normal cell lines in a ROS-dependent manner. Chem Biol Interact. 2023 Sep 1;382:110642. doi: 10.1016/j.cbi.2023.110642. Epub 2023 Jul 23.
• [13] Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) in human melanoma and identification of the therapeutic potential of resveratrol as an APE/Ref-1 inhibitor. Mol Cancer Ther. 2005 Dec;4(12):1923-35. doi: 10.1158/1535-7163.MCT-05-0229.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [16] Human AP endonuclease (APE1/Ref-1) and its acetylation regulate YB-1-p300 recruitment and RNA polymerase II loading in the drug-induced activation of multidrug resistance gene MDR1. Oncogene. 2011 Jan 27;30(4):482-93. doi: 10.1038/onc.2010.435. Epub 2010 Sep 20.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] APE1 modulates cellular responses to organophosphate pesticide-induced oxidative damage in non-small cell lung carcinoma A549 cells. Mol Cell Biochem. 2018 Apr;441(1-2):201-216.
• [19] Susceptibility to arsenic-induced skin lesions from polymorphisms in base excision repair genes. Carcinogenesis. 2007 Jul;28(7):1520-5. doi: 10.1093/carcin/bgm063. Epub 2007 Mar 20.
• [20] Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res. 2009 Jun;7(6):897-906. doi: 10.1158/1541-7786.MCR-08-0519. Epub 2009 May 26.
• [21] A dominant-negative form of the major human abasic endonuclease enhances cellular sensitivity to laboratory and clinical DNA-damaging agents. Mol Cancer Res. 2007 Jan;5(1):61-70. doi: 10.1158/1541-7786.MCR-06-0329.
• [22] Editor's Highlight: Base Excision Repair Variants and Pesticide Exposure Increase Parkinson's Disease Risk. Toxicol Sci. 2017 Jul 1;158(1):188-198. doi: 10.1093/toxsci/kfx086.
• [23] APE1/Ref-1 prevents oxidative inactivation of ERK for G1-to-S progression following lead acetate exposure. Toxicology. 2013 Mar 8;305:120-9. doi: 10.1016/j.tox.2013.01.010. Epub 2013 Jan 28.