Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT51O0CF)

• DOT Name: DNA topoisomerase 1 (TOP1)
• Synonyms: EC 5.6.2.1; DNA topoisomerase I
• Gene Name: TOP1
• UniProt ID: TOP1_HUMAN
• PDB ID: 1A31; 1A35; 1A36; 1EJ9; 1K4S; 1K4T; 1LPQ; 1NH3; 1R49; 1RR8; 1RRJ; 1SC7; 1SEU; 1T8I; 1TL8
• EC Number: 5.6.2.1
• Pfam ID: PF14370 ; PF01028 ; PF02919
• Sequence:
  MSGDHLHNDSQIEADFRLNDSHKHKDKHKDREHRHKEHKKEKDREKSKHSNSEHKDSEKK
  HKEKEKTKHKDGSSEKHKDKHKDRDKEKRKEEKVRASGDAKIKKEKENGFSSPPQIKDEP
  EDDGYFVPPKEDIKPLKRPRDEDDADYKPKKIKTEDTKKEKKRKLEEEEDGKLKKPKNKD
  KDKKVPEPDNKKKKPKKEEEQKWKWWEEERYPEGIKWKFLEHKGPVFAPPYEPLPENVKF
  YYDGKVMKLSPKAEEVATFFAKMLDHEYTTKEIFRKNFFKDWRKEMTNEEKNIITNLSKC
  DFTQMSQYFKAQTEARKQMSKEEKLKIKEENEKLLKEYGFCIMDNHKERIANFKIEPPGL
  FRGRGNHPKMGMLKRRIMPEDIIINCSKDAKVPSPPPGHKWKEVRHDNKVTWLVSWTENI
  QGSIKYIMLNPSSRIKGEKDWQKYETARRLKKCVDKIRNQYREDWKSKEMKVRQRAVALY
  FIDKLALRAGNEKEEGETADTVGCCSLRVEHINLHPELDGQEYVVEFDFLGKDSIRYYNK
  VPVEKRVFKNLQLFMENKQPEDDLFDRLNTGILNKHLQDLMEGLTAKVFRTYNASITLQQ
  QLKELTAPDENIPAKILSYNRANRAVAILCNHQRAPPKTFEKSMMNLQTKIDAKKEQLAD
  ARRDLKSAKADAKVMKDAKTKKVVESKKKAVQRLEEQLMKLEVQATDREENKQIALGTSK
  LNYLDPRITVAWCKKWGVPIEKIYNKTQREKFAWAIDMADEDYEF
• 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-(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. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Involved in the circadian transcription of the core circadian clock component BMAL1 by altering the chromatin structure around the ROR response elements (ROREs) on the BMAL1 promoter.
• Tissue Specificity: Endothelial cells.
• Reactome Pathway: SUMOylation of DNA replication proteins (R-HSA-4615885)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	DNA topoisomerase 1 (TOP1) increases the Cytogenetic investigations ADR of Doxorubicin.	[25]
Mitoxantrone	DMM39BF	Approved	DNA topoisomerase 1 (TOP1) increases the Cytogenetic investigations ADR of Mitoxantrone.	[25]
Prednisolone	DMQ8FR2	Approved	DNA topoisomerase 1 (TOP1) increases the Apoptosis ADR of Prednisolone.	[25]
Amsacrine	DMZKYIV	Approved	DNA topoisomerase 1 (TOP1) increases the Cytogenetic investigations ADR of Amsacrine.	[25]
Teniposide	DMLW57T	Approved	DNA topoisomerase 1 (TOP1) increases the Cytogenetic investigations ADR of Teniposide.	[25]

34 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 DNA topoisomerase 1 (TOP1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA topoisomerase 1 (TOP1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA topoisomerase 1 (TOP1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DNA topoisomerase 1 (TOP1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA topoisomerase 1 (TOP1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA topoisomerase 1 (TOP1).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DNA topoisomerase 1 (TOP1).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of DNA topoisomerase 1 (TOP1).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DNA topoisomerase 1 (TOP1).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of DNA topoisomerase 1 (TOP1).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of DNA topoisomerase 1 (TOP1).	[7]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of DNA topoisomerase 1 (TOP1).	[11]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of DNA topoisomerase 1 (TOP1).	[6]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of DNA topoisomerase 1 (TOP1).	[12]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of DNA topoisomerase 1 (TOP1).	[5]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of DNA topoisomerase 1 (TOP1).	[5]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of DNA topoisomerase 1 (TOP1).	[13]
Lapatinib	DM3BH1Y	Approved	Lapatinib decreases the expression of DNA topoisomerase 1 (TOP1).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DNA topoisomerase 1 (TOP1).	[15]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the activity of DNA topoisomerase 1 (TOP1).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of DNA topoisomerase 1 (TOP1).	[3]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of DNA topoisomerase 1 (TOP1).	[10]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of DNA topoisomerase 1 (TOP1).	[6]
URSOLIC ACID	DM4SOAW	Phase 2	URSOLIC ACID decreases the activity of DNA topoisomerase 1 (TOP1).	[17]
Delphinidin	DMS2WIN	Phase 2	Delphinidin decreases the activity of DNA topoisomerase 1 (TOP1).	[18]
R-roscovitine	DMSH108	Phase 2	R-roscovitine increases the expression of DNA topoisomerase 1 (TOP1).	[13]
BETULINIC ACID	DMBUI2A	Phase 1	BETULINIC ACID decreases the activity of DNA topoisomerase 1 (TOP1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA topoisomerase 1 (TOP1).	[21]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of DNA topoisomerase 1 (TOP1).	[22]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of DNA topoisomerase 1 (TOP1).	[23]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of DNA topoisomerase 1 (TOP1).	[23]
OLEANOLIC_ACID	DMWDMJ3	Investigative	OLEANOLIC_ACID decreases the expression of DNA topoisomerase 1 (TOP1).	[24]
PALMATINE	DMJCOKV	Investigative	PALMATINE decreases the activity of DNA topoisomerase 1 (TOP1).	[16]
3-acetyl-11-keto-beta-boswellic acid	DMGO2D7	Investigative	3-acetyl-11-keto-beta-boswellic acid decreases the activity of DNA topoisomerase 1 (TOP1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of DNA topoisomerase 1 (TOP1).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of DNA topoisomerase 1 (TOP1).	[20]

References

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• [19] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
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