Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ22LIT)

• DOT Name: DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2)
• Synonyms: EC 3.1.11.2; AP endonuclease XTH2; APEX nuclease 2; APEX nuclease-like 2; Apurinic-apyrimidinic endonuclease 2; AP endonuclease 2
• Gene Name: APEX2
• Related Disease:
  Dengue
  Epilepsy
  Osteoarthritis
  Schizophrenia
  Plasma cell myeloma
  Coronary heart disease
  Ebola virus infection
• UniProt ID: APEX2_HUMAN
• EC Number: 3.1.11.2
• Pfam ID: PF03372 ; PF06839
• Sequence:
  MLRVVSWNINGIRRPLQGVANQEPSNCAAVAVGRILDELDADIVCLQETKVTRDALTEPL
  AIVEGYNSYFSFSRNRSGYSGVATFCKDNATPVAAEEGLSGLFATQNGDVGCYGNMDEFT
  QEELRALDSEGRALLTQHKIRTWEGKEKTLTLINVYCPHADPGRPERLVFKMRFYRLLQI
  RAEALLAAGSHVIILGDLNTAHRPIDHWDAVNLECFEEDPGRKWMDSLLSNLGCQSASHV
  GPFIDSYRCFQPKQEGAFTCWSAVTGARHLNYGSRLDYVLGDRTLVIDTFQASFLLPEVM
  GSDHCPVGAVLSVSSVPAKQCPPLCTRFLPEFAGTQLKILRFLVPLEQSPVLEQSTLQHN
  NQTRVQTCQNKAQVRSTRPQPSQVGSSRGQKNLKSYFQPSPSCPQASPDIELPSLPLMSA
  LMTPKTPEEKAVAKVVKGQAKTSEAKDEKELRTSFWKSVLAGPLRTPLCGGHREPCVMRT
  VKKPGPNLGRRFYMCARPRGPPTDPSSRCNFFLWSRPS
• Function: Functions as a weak 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 displays double-stranded DNA 3'-5' exonuclease, 3'-phosphodiesterase activities. Shows robust 3'-5' exonuclease activity on 3'-recessed heteroduplex DNA and is able to remove mismatched nucleotides preferentially. Also exhibits 3'-5' exonuclease activity on a single nucleotide gap containing heteroduplex DNA and on blunt-ended substrates. Shows fairly strong 3'-phosphodiesterase activity involved in the removal of 3'-damaged termini formed in DNA by oxidative agents. In the nucleus functions in the PCNA-dependent BER pathway. Plays a role in reversing blocked 3' DNA ends, problematic lesions that preclude DNA synthesis. Required for somatic hypermutation (SHM) and DNA cleavage step of class switch recombination (CSR) of immunoglobulin genes. Required for proper cell cycle progression during proliferation of peripheral lymphocytes.
• Tissue Specificity: Highly expressed in brain and kidney. Weakly expressed in the fetal brain.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dengue	DISKH221	Strong	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Biomarker	[2]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[3]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[4]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[5]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[6]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[14]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[18]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA-(apurinic or apyrimidinic site) endonuclease 2 (APEX2).	[16]

References

• [1] Dengue Virus Hijacks a Noncanonical Oxidoreductase Function of a Cellular Oligosaccharyltransferase Complex.mBio. 2017 Jul 18;8(4):e00939-17. doi: 10.1128/mBio.00939-17.
• [2] Autoimmune Epilepsy.Neurotherapeutics. 2019 Jul;16(3):685-702. doi: 10.1007/s13311-019-00750-3.
• [3] The DNA repair enzyme apurinic/apyrimidinic endonuclease (Apex nuclease) 2 has the potential to protect against down-regulation of chondrocyte activity in osteoarthritis.Int J Mol Sci. 2014 Aug 25;15(9):14921-34. doi: 10.3390/ijms150914921.
• [4] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [5] Role of apurinic/apyrimidinic nucleases in the regulation of homologous recombination in myeloma: mechanisms and translational significance.Blood Cancer J. 2018 Sep 25;8(10):92. doi: 10.1038/s41408-018-0129-9.
• [6] Fibrinogen beta variants confer protection against coronary artery disease in a Greek case-control study.BMC Med Genet. 2010 Feb 18;11:28. doi: 10.1186/1471-2350-11-28.
• [7] Periplasmic Nanobody-APEX2 Fusions Enable Facile Visualization of Ebola, Marburg, and Mngl virus Nucleoproteins, Alluding to Similar Antigenic Landscapes among Marburgvirus and Dianlovirus.Viruses. 2019 Apr 20;11(4):364. doi: 10.3390/v11040364.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Combined effects of arsenic and palmitic acid on oxidative stress and lipid metabolism disorder in human hepatoma HepG2 cells. Sci Total Environ. 2021 May 15;769:144849. doi: 10.1016/j.scitotenv.2020.144849. Epub 2021 Jan 19.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [15] Comparison of gene expression profiles in HepG2 cells exposed to arsenic, cadmium, nickel, and three model carcinogens for investigating the mechanisms of metal carcinogenesis. Environ Mol Mutagen. 2009 Jan;50(1):46-59.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.