Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3CKUI9)

• DOT Name: DNA topoisomerase 3-alpha (TOP3A)
• Synonyms: EC 5.6.2.1; DNA topoisomerase III alpha
• Gene Name: TOP3A
• Related Disease:
  Isolated congenital microcephaly
  Microcephaly, growth restriction, and increased sister chromatid exchange 2
  Advanced cancer
  Astrocytoma
  Bladder cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Hepatitis C virus infection
  Lung adenocarcinoma
  Lung squamous cell carcinoma
  Melanoma
  Multiple sclerosis
  Non-small-cell lung cancer
  Osteosarcoma
  Premature aging syndrome
  Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5
  Urinary bladder cancer
  Urinary bladder neoplasm
  Werner syndrome
  Bloom syndrome
  Mitochondrial disease
  Progressive external ophthalmoplegia
• UniProt ID: TOP3A_HUMAN
• PDB ID: 4CGY; 4CHT
• EC Number: 5.6.2.1
• Pfam ID: PF01131 ; PF01751 ; PF01396 ; PF06839
• Sequence:
  MIFPVARYALRWLRRPEDRAFSRAAMEMALRGVRKVLCVAEKNDAAKGIADLLSNGRMRR
  REGLSKFNKIYEFDYHLYGQNVTMVMTSVSGHLLAHDFQMQFRKWQSCNPLVLFEAEIEK
  YCPENFVDIKKTLERETRQCQALVIWTDCDREGENIGFEIIHVCKAVKPNLQVLRARFSE
  ITPHAVRTACENLTEPDQRVSDAVDVRQELDLRIGAAFTRFQTLRLQRIFPEVLAEQLIS
  YGSCQFPTLGFVVERFKAIQAFVPEIFHRIKVTHDHKDGIVEFNWKRHRLFNHTACLVLY
  QLCVEDPMATVVEVRSKPKSKWRPQALDTVELEKLASRKLRINAKETMRIAEKLYTQGYI
  SYPRTETNIFPRDLNLTVLVEQQTPDPRWGAFAQSILERGGPTPRNGNKSDQAHPPIHPT
  KYTNNLQGDEQRLYEFIVRHFLACCSQDAQGQETTVEIDIAQERFVAHGLMILARNYLDV
  YPYDHWSDKILPVYEQGSHFQPSTVEMVDGETSPPKLLTEADLIALMEKHGIGTDATHAE
  HIETIKARMYVGLTPDKRFLPGHLGMGLVEGYDSMGYEMSKPDLRAELEADLKLICDGKK
  DKFVVLRQQVQKYKQVFIEAVAKAKKLDEALAQYFGNGTELAQQEDIYPAMPEPIRKCPQ
  CNKDMVLKTKKNGGFYLSCMGFPECRSAVWLPDSVLEASRDSSVCPVCQPHPVYRLKLKF
  KRGSLPPTMPLEFVCCIGGCDDTLREILDLRFSGGPPRASQPSGRLQANQSLNRMDNSQH
  PQPADSRQTGSSKALAQTLPPPTAAGESNSVTCNCGQEAVLLTVRKEGPNRGRQFFKCNG
  GSCNFFLWADSPNPGAGGPPALAYRPLGASLGCPPGPGIHLGGFGNPGDGSGSGTSCLCS
  QPSVTRTVQKDGPNKGRQFHTCAKPREQQCGFFQWVDENTAPGTSGAPSWTGDRGRTLES
  EARSKRPRASSSDMGSTAKKPRKCSLCHQPGHTRPFCPQNR
• Function: Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(5'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 3'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone. As an essential component of the RMI complex it is involved in chromosome separation and the processing of homologous recombination intermediates to limit DNA crossover formation in cells. Has DNA decatenation activity. It is required for mtDNA decatenation and segregation after completion of replication, in a process that does not require BLM, RMI1 and RMI2.
• Tissue Specificity: High expression is found in testis, heart, skeletal muscle and pancreas.
• KEGG Pathway:
  Homologous recombi.tion (hsa03440)
  Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  Homologous DNA Pairing and Strand Exchange (R-HSA-5693579)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Meiotic recombination (R-HSA-912446)
  Defective homologous recombination repair (HRR) due to BRCA1 loss of function (R-HSA-9701192)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function (R-HSA-9704331)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function (R-HSA-9704646)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Impaired BRCA2 binding to PALB2 (R-HSA-9709603)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isolated congenital microcephaly	DISUXHZ6	Definitive	Genetic Variation	[1]
Microcephaly, growth restriction, and increased sister chromatid exchange 2	DISC5WNZ	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Astrocytoma	DISL3V18	Strong	Altered Expression	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[7]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[7]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[3]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Premature aging syndrome	DIS51AGT	Strong	Biomarker	[9]
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5	DISCA6TS	Strong	Autosomal recessive	[10]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Werner syndrome	DISZY45W	Strong	Biomarker	[9]
Bloom syndrome	DISKXQ7J	moderate	Genetic Variation	[1]
Mitochondrial disease	DISKAHA3	moderate	Genetic Variation	[10]
Progressive external ophthalmoplegia	DISX4ATI	moderate	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of DNA topoisomerase 3-alpha (TOP3A).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA topoisomerase 3-alpha (TOP3A).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DNA topoisomerase 3-alpha (TOP3A).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA topoisomerase 3-alpha (TOP3A).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of DNA topoisomerase 3-alpha (TOP3A).	[14]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of DNA topoisomerase 3-alpha (TOP3A).	[12]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of DNA topoisomerase 3-alpha (TOP3A).	[12]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of DNA topoisomerase 3-alpha (TOP3A).	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of DNA topoisomerase 3-alpha (TOP3A).	[16]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of DNA topoisomerase 3-alpha (TOP3A).	[17]

References

• [1] Mutations in TOP3A Cause a Bloom Syndrome-like Disorder.Am J Hum Genet. 2018 Aug 2;103(2):221-231. doi: 10.1016/j.ajhg.2018.07.001. Epub 2018 Jul 26.
• [2] 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.
• [3] Association between polymorphisms in RMI1, TOP3A, and BLM and risk of cancer, a case-control study.BMC Cancer. 2009 May 11;9:140. doi: 10.1186/1471-2407-9-140.
• [4] Higher topoisomerase 2 alpha gene transcript levels predict better prognosis in GBM patients receiving temozolomide chemotherapy: identification of temozolomide as a TOP2A inhibitor.J Neurooncol. 2012 Apr;107(2):289-97. doi: 10.1007/s11060-011-0758-3. Epub 2011 Nov 19.
• [5] Amplification of 17p11.2 approximately p12, including PMP22, TOP3A, and MAPK7, in high-grade osteosarcoma.Cancer Genet Cytogenet. 2002 Dec;139(2):91-6. doi: 10.1016/s0165-4608(02)00627-1.
• [6] Online symptom checker diagnostic and triage accuracy for HIV and hepatitis C.Epidemiol Infect. 2019 Jan;147:e104. doi: 10.1017/S0950268819000268.
• [7] Mining expression and prognosis of topoisomerase isoforms in non-small-cell lung cancer by using Oncomine and Kaplan-Meier plotter.PLoS One. 2017 Mar 29;12(3):e0174515. doi: 10.1371/journal.pone.0174515. eCollection 2017.
• [8] Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.Sci Adv. 2016 Jun 17;2(6):e1501678. doi: 10.1126/sciadv.1501678. eCollection 2016 Jun.
• [9] WRN helicase defective in the premature aging disorder Werner syndrome genetically interacts with topoisomerase 3 and restores the top3 slow growth phenotype of sgs1 top3.Aging (Albany NY). 2009 Feb 5;1(2):219-33. doi: 10.18632/aging.100020.
• [10] Topoisomerase 3 Is Required for Decatenation and Segregation of Human mtDNA. Mol Cell. 2018 Jan 4;69(1):9-23.e6. doi: 10.1016/j.molcel.2017.11.033. Epub 2017 Dec 28.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [13] 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.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] 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.
• [16] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [17] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.