Details of Drug Off-Target (DOT)

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

• DOT Name: DNA topoisomerase 3-beta-1 (TOP3B)
• Synonyms: EC 5.6.2.1; DNA topoisomerase III beta-1
• Gene Name: TOP3B
• Related Disease:
  Advanced cancer
  Autism
  Fragile X syndrome
  Kidney cancer
  Lung cancer
  Renal carcinoma
  Schizophrenia
  Epilepsy
  Juvenile myoclonic epilepsy
  Neurodevelopmental disorder
• UniProt ID: TOP3B_HUMAN
• PDB ID: 5GVC; 5GVE
• EC Number: 5.6.2.1
• Pfam ID: PF01131 ; PF01751
• Sequence:
  MKTVLMVAEKPSLAQSIAKILSRGSLSSHKGLNGACSVHEYTGTFAGQPVRFKMTSVCGH
  VMTLDFLGKYNKWDKVDPAELFSQAPTEKKEANPKLNMVKFLQVEGRGCDYIVLWLDCDK
  EGENICFEVLDAVLPVMNKAHGGEKTVFRARFSSITDTDICNAMACLGEPDHNEALSVDA
  RQELDLRIGCAFTRFQTKYFQGKYGDLDSSLISFGPCQTPTLGFCVERHDKIQSFKPETY
  WVLQAKVNTDKDRSLLLDWDRVRVFDREIAQMFLNMTKLEKEAQVEATSRKEKAKQRPLA
  LNTVEMLRVASSSLGMGPQHAMQTAERLYTQGYISYPRTETTHYPENFDLKGSLRQQANH
  PYWADTVKRLLAEGINRPRKGHDAGDHPPITPMKSATEAELGGDAWRLYEYITRHFIATV
  SHDCKYLQSTISFRIGPELFTCSGKTVLSPGFTEVMPWQSVPLEESLPTCQRGDAFPVGE
  VKMLEKQTNPPDYLTEAELITLMEKHGIGTDASIPVHINNICQRNYVTVESGRRLKPTNL
  GIVLVHGYYKIDAELVLPTIRSAVEKQLNLIAQGKADYRQVLGHTLDVFKRKFHYFVDSI
  AGMDELMEVSFSPLAATGKPLSRCGKCHRFMKYIQAKPSRLHCSHCDETYTLPQNGTIKL
  YKELRCPLDDFELVLWSSGSRGKSYPLCPYCYNHPPFRDMKKGMGCNECTHPSCQHSLSM
  LGIGQCVECESGVLVLDPTSGPKWKVACNKCNVVAHCFENAHRVRVSADTCSVCEAALLD
  VDFNKAKSPLPGDETQHMGCVFCDPVFQELVELKHAASCHPMHRGGPGRRQGRGRGRARR
  PPGKPNPRRPKDKMSALAAYFV
• 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 than 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. Possesses negatively supercoiled DNA relaxing activity.
• Tissue Specificity: Isoform 1 is found in testis, heart and skeletal muscle. A 4 kb transcript which probably represents isoform 2 is found in thymus, kidney and pancreas.
• KEGG Pathway:
  Homologous recombi.tion (hsa03440)
  Fanconi anemia pathway (hsa03460)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[3]
Kidney cancer	DISBIPKM	Strong	Genetic Variation	[1]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Renal carcinoma	DISER9XT	Strong	Genetic Variation	[1]
Schizophrenia	DISSRV2N	Strong	Biomarker	[2]
Epilepsy	DISBB28L	Limited	Biomarker	[2]
Juvenile myoclonic epilepsy	DISYXV1N	Limited	Biomarker	[2]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of DNA topoisomerase 3-beta-1 (TOP3B).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of DNA topoisomerase 3-beta-1 (TOP3B).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA topoisomerase 3-beta-1 (TOP3B).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Aspirin increases the expression of DNA topoisomerase 3-beta-1 (TOP3B).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA topoisomerase 3-beta-1 (TOP3B).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA topoisomerase 3-beta-1 (TOP3B).	[9]

References

• [1] Loss of TOP3B leads to increased R-loop formation and genome instability.Open Biol. 2019 Dec;9(12):190222. doi: 10.1098/rsob.190222. Epub 2019 Dec 4.
• [2] TOP3B: A Novel Candidate Gene in Juvenile Myoclonic Epilepsy?.Cytogenet Genome Res. 2018;154(1):1-5. doi: 10.1159/000486945. Epub 2018 Feb 28.
• [3] Deletion of TOP3B Is Associated with Cognitive Impairment and Facial Dysmorphism.Cytogenet Genome Res. 2016;150(2):106-111. doi: 10.1159/000452815. Epub 2016 Nov 24.
• [4] Transcriptional profiling of targets for combination therapy of lung carcinoma with paclitaxel and mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor.Cancer Res. 2003 Aug 15;63(16):5095-104.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] 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.
• [7] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] 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.
• [10] 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.