Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2H77ID)

• DOT Name: DNA topoisomerase I, mitochondrial (TOP1MT)
• Synonyms: TOP1mt; EC 5.6.2.1
• Gene Name: TOP1MT
• Related Disease:
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Colon carcinoma
  Liver cancer
  Lung carcinoma
  Neoplasm
• UniProt ID: TOP1M_HUMAN
• EC Number: 5.6.2.1
• Pfam ID: PF14370 ; PF01028 ; PF02919
• Sequence:
  MRVVRLLRLRAALTLLGEVPRRPASRGVPGSRRTQKGSGARWEKEKHEDGVKWRQLEHKG
  PYFAPPYEPLPDGVRFFYEGRPVRLSVAAEEVATFYGRMLDHEYTTKEVFRKNFFNDWRK
  EMAVEEREVIKSLDKCDFTEIHRYFVDKAAARKVLSREEKQKLKEEAEKLQQEFGYCILD
  GHQEKIGNFKIEPPGLFRGRGDHPKMGMLKRRITPEDVVINCSRDSKIPEPPAGHQWKEV
  RSDNTVTWLAAWTESVQNSIKYIMLNPCSKLKGETAWQKFETARRLRGFVDEIRSQYRAD
  WKSREMKTRQRAVALYFIDKLALRAGNEKEDGEAADTVGCCSLRVEHVQLHPEADGCQHV
  VEFDFLGKDCIRYYNRVPVEKPVYKNLQLFMENKDPRDDLFDRLTTTSLNKHLQELMDGL
  TAKVFRTYNASITLQEQLRALTRAEDSIAAKILSYNRANRVVAILCNHQRATPSTFEKSM
  QNLQTKIQAKKEQVAEARAELRRARAEHKAQGDGKSRSVLEKKRRLLEKLQEQLAQLSVQ
  ATDKEENKQVALGTSKLNYLDPRISIAWCKRFRVPVEKIYSKTQRERFAWALAMAGEDFE
  F
• Function: Releases the supercoiling and torsional tension of DNA introduced during duplication of mitochondrial DNA 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-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then rotates around the intact phosphodiester bond on the opposing strand, thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone.
• Tissue Specificity: Ubiquitous; highest in skeletal muscle, heart, brain and fetal liver.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Liver cancer	DISDE4BI	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]

2 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 I, mitochondrial (TOP1MT).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of DNA topoisomerase I, mitochondrial (TOP1MT).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA topoisomerase I, mitochondrial (TOP1MT).	[5]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of DNA topoisomerase I, mitochondrial (TOP1MT).	[6]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of DNA topoisomerase I, mitochondrial (TOP1MT).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DNA topoisomerase I, mitochondrial (TOP1MT).	[7]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of DNA topoisomerase I, mitochondrial (TOP1MT).	[8]

References

• [1] Distribution bias and biochemical characterization of TOP1MT single nucleotide variants.Sci Rep. 2017 Aug 17;7(1):8614. doi: 10.1038/s41598-017-09258-2.
• [2] The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis.Nat Commun. 2019 Jan 8;10(1):83. doi: 10.1038/s41467-018-07922-3.
• [3] Lack of mitochondrial topoisomerase I (TOP1mt) impairs liver regeneration.Proc Natl Acad Sci U S A. 2015 Sep 8;112(36):11282-7. doi: 10.1073/pnas.1511016112. Epub 2015 Aug 24.
• [4] 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.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [7] 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.
• [8] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [9] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.