Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIN7L7I)

• DOT Name: Exonuclease V (EXO5)
• Synonyms: Exo V; hExo5; EC 3.1.-.-; Defects in morphology protein 1 homolog
• Gene Name: EXO5
• Related Disease:
  Advanced cancer
  Prostate cancer
  Prostate carcinoma
  Testicular cancer
• UniProt ID: EXO5_HUMAN
• PDB ID: 7LW7; 7LW8; 7LW9; 7LWA
• EC Number: 3.1.-.-
• Pfam ID: PF09810
• Sequence:
  MAETREEETVSAEASGFSDLSDSEFLEFLDLEDAQESKALVNMPGPSSESLGKDDKPISL
  QNWKRGLDILSPMERFHLKYLYVTDLATQNWCELQTAYGKELPGFLAPEKAAVLDTGASI
  HLARELELHDLVTVPVTTKEDAWAIKFLNILLLIPTLQSEGHIREFPVFGEGEGVLLVGV
  IDELHYTAKGELELAELKTRRRPMLPLEAQKKKDCFQVSLYKYIFDAMVQGKVTPASLIH
  HTKLCLEKPLGPSVLRHAQQGGFSVKSLGDLMELVFLSLTLSDLPVIDILKIEYIHQETA
  TVLGTEIVAFKEKEVRAKVQHYMAYWMGHREPQGVDVEEAWKCRTCTYADICEWRKGSGV
  LSSTLAPQVKKAK
• Function: Single-stranded DNA (ssDNA) bidirectional exonuclease involved in DNA repair. Probably involved in DNA repair following ultraviolet (UV) irradiation and interstrand cross-links (ICLs) damage. Has both 5'-3' and 3'-5' exonuclease activities with a strong preference for 5'-ends. Acts as a sliding exonuclease that loads at ssDNA ends and then slides along the ssDNA prior to cutting; however the sliding and the 3'-5' exonuclease activities are abolished upon binding to the replication protein A (RPA) complex that enforces 5'-directionality activity.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[2]
Testicular cancer	DIS6HNYO	Strong	Biomarker	[3]

11 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 Exonuclease V (EXO5).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Exonuclease V (EXO5).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Exonuclease V (EXO5).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Exonuclease V (EXO5).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Exonuclease V (EXO5).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Exonuclease V (EXO5).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Exonuclease V (EXO5).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Exonuclease V (EXO5).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Exonuclease V (EXO5).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Exonuclease V (EXO5).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Exonuclease V (EXO5).	[14]

2 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 decreases the methylation of Exonuclease V (EXO5).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Exonuclease V (EXO5).	[15]

References

• [1] Detecting episomal or integrated human papillomavirus 16 DNA using an exonuclease V-qPCR-based assay.Virology. 2019 Nov;537:149-156. doi: 10.1016/j.virol.2019.08.021. Epub 2019 Aug 22.
• [2] Functional deficiency of DNA repair gene EXO5 results in androgen-induced genomic instability and prostate tumorigenesis.Oncogene. 2020 Feb;39(6):1246-1259. doi: 10.1038/s41388-019-1061-6. Epub 2019 Oct 15.
• [3] Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer.Int J Cancer. 2018 Oct 15;143(8):1954-1962. doi: 10.1002/ijc.31604. Epub 2018 Aug 9.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.