Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDHKQZ8)

• DOT Name: DNA topoisomerase 2-beta (TOP2B)
• Synonyms: EC 5.6.2.2; DNA topoisomerase II, beta isozyme
• Gene Name: TOP2B
• Related Disease: B-cell immunodeficiency, distal limb anomalies, and urogenital malformations
• UniProt ID: TOP2B_HUMAN
• PDB ID: 3QX3; 4G0U; 4G0V; 4G0W; 4J3N; 5GWI; 5GWJ; 5ZAD; 5ZEN; 5ZQF; 5ZRF; 7QFN; 7QFO; 7ZBG
• EC Number: 5.6.2.2
• Pfam ID: PF00204 ; PF00521 ; PF08070 ; PF02518 ; PF01751 ; PF16898
• Sequence:
  MAKSGGCGAGAGVGGGNGALTWVTLFDQNNAAKKEESETANKNDSSKKLSVERVYQKKTQ
  LEHILLRPDTYIGSVEPLTQFMWVYDEDVGMNCREVTFVPGLYKIFDEILVNAADNKQRD
  KNMTCIKVSIDPESNIISIWNNGKGIPVVEHKVEKVYVPALIFGQLLTSSNYDDDEKKVT
  GGRNGYGAKLCNIFSTKFTVETACKEYKHSFKQTWMNNMMKTSEAKIKHFDGEDYTCITF
  QPDLSKFKMEKLDKDIVALMTRRAYDLAGSCRGVKVMFNGKKLPVNGFRSYVDLYVKDKL
  DETGVALKVIHELANERWDVCLTLSEKGFQQISFVNSIATTKGGRHVDYVVDQVVGKLIE
  VVKKKNKAGVSVKPFQVKNHIWVFINCLIENPTFDSQTKENMTLQPKSFGSKCQLSEKFF
  KAASNCGIVESILNWVKFKAQTQLNKKCSSVKYSKIKGIPKLDDANDAGGKHSLECTLIL
  TEGDSAKSLAVSGLGVIGRDRYGVFPLRGKILNVREASHKQIMENAEINNIIKIVGLQYK
  KSYDDAESLKTLRYGKIMIMTDQDQDGSHIKGLLINFIHHNWPSLLKHGFLEEFITPIVK
  ASKNKQELSFYSIPEFDEWKKHIENQKAWKIKYYKGLGTSTAKEAKEYFADMERHRILFR
  YAGPEDDAAITLAFSKKKIDDRKEWLTNFMEDRRQRRLHGLPEQFLYGTATKHLTYNDFI
  NKELILFSNSDNERSIPSLVDGFKPGQRKVLFTCFKRNDKREVKVAQLAGSVAEMSAYHH
  GEQALMMTIVNLAQNFVGSNNINLLQPIGQFGTRLHGGKDAASPRYIFTMLSTLARLLFP
  AVDDNLLKFLYDDNQRVEPEWYIPIIPMVLINGAEGIGTGWACKLPNYDAREIVNNVRRM
  LDGLDPHPMLPNYKNFKGTIQELGQNQYAVSGEIFVVDRNTVEITELPVRTWTQVYKEQV
  LEPMLNGTDKTPALISDYKEYHTDTTVKFVVKMTEEKLAQAEAAGLHKVFKLQTTLTCNS
  MVLFDHMGCLKKYETVQDILKEFFDLRLSYYGLRKEWLVGMLGAESTKLNNQARFILEKI
  QGKITIENRSKKDLIQMLVQRGYESDPVKAWKEAQEKAAEEDETQNQHDDSSSDSGTPSG
  PDFNYILNMSLWSLTKEKVEELIKQRDAKGREVNDLKRKSPSDLWKEDLAAFVEELDKVE
  SQEREDVLAGMSGKAIKGKVGKPKVKKLQLEETMPSPYGRRIIPEITAMKADASKKLLKK
  KKGDLDTAAVKVEFDEEFSGAPVEGAGEEALTPSVPINKGPKPKREKKEPGTRVRKTPTS
  SGKPSAKKVKKRNPWSDDESKSESDLEETEPVVIPRDSLLRRAAAERPKYTFDFSEEEDD
  DADDDDDDNNDLEELKVKASPITNDGEDEFVPSDGLDKDEYTFSPGKSKATPEKSLHDKK
  SQDFGNLFSFPSYSQKSEDDSAKFDSNEEDSASVFSPSFGLKQTDKVPSKTVAAKKGKPS
  SDTVPKPKRAPKQKKVVEAVNSDSDSEFGIPKKTTTPKGKGRGAKKRKASGSENEGDYNP
  GRKTSKTTSKKPKKTSFDQDSDVDIFPSDFPTEPPSLPRTGRARKEVKYFAESDEEEDDV
  DFAMFN
• Function: Key decatenating enzyme that alters DNA topology by binding to two double-stranded DNA molecules, generating a double-stranded break in one of the strands, passing the intact strand through the broken strand, and religating the broken strand. Plays a role in B-cell differentiation.
• Tissue Specificity: Expressed in the tonsil, spleen, lymph node, thymus, skin, pancreas, testis, colon, kidney, liver, brain and lung . Also found in breast, colon and lung carcinomas, Hodgkin's disease, large-cell non-Hodgkin's lymphoma, lymphocytic lymphomas and seminomas .
• KEGG Pathway: Platinum drug resistance (hsa01524)
• Reactome Pathway: SUMOylation of DNA replication proteins (R-HSA-4615885)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell immunodeficiency, distal limb anomalies, and urogenital malformations	DIS37KZJ	Moderate	Autosomal dominant	[1]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	DNA topoisomerase 2-beta (TOP2B) decreases the response to substance of Doxorubicin.	[23]
Arsenic trioxide	DM61TA4	Approved	DNA topoisomerase 2-beta (TOP2B) increases the response to substance of Arsenic trioxide.	[24]
Amsacrine	DMZKYIV	Approved	DNA topoisomerase 2-beta (TOP2B) decreases the response to substance of Amsacrine.	[25]
Ellipticine	DMHPYSM	Investigative	DNA topoisomerase 2-beta (TOP2B) decreases the response to substance of Ellipticine.	[23]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	DNA topoisomerase 2-beta (TOP2B) increases the hydrolysis of Adenosine triphosphate.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of DNA topoisomerase 2-beta (TOP2B).	[2]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of DNA topoisomerase 2-beta (TOP2B).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of DNA topoisomerase 2-beta (TOP2B).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA topoisomerase 2-beta (TOP2B).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of DNA topoisomerase 2-beta (TOP2B).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA topoisomerase 2-beta (TOP2B).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA topoisomerase 2-beta (TOP2B).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA topoisomerase 2-beta (TOP2B).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA topoisomerase 2-beta (TOP2B).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of DNA topoisomerase 2-beta (TOP2B).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DNA topoisomerase 2-beta (TOP2B).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of DNA topoisomerase 2-beta (TOP2B).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of DNA topoisomerase 2-beta (TOP2B).	[5]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the activity of DNA topoisomerase 2-beta (TOP2B).	[10]
Etoposide	DMNH3PG	Approved	Etoposide decreases the activity of DNA topoisomerase 2-beta (TOP2B).	[11]
Menthol	DMG2KW7	Approved	Menthol increases the expression of DNA topoisomerase 2-beta (TOP2B).	[12]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of DNA topoisomerase 2-beta (TOP2B).	[3]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of DNA topoisomerase 2-beta (TOP2B).	[13]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of DNA topoisomerase 2-beta (TOP2B).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of DNA topoisomerase 2-beta (TOP2B).	[15]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of DNA topoisomerase 2-beta (TOP2B).	[5]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA topoisomerase 2-beta (TOP2B).	[20]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the activity of DNA topoisomerase 2-beta (TOP2B).	[11]
Benzoquinone	DMNBA0G	Investigative	Benzoquinone affects the activity of DNA topoisomerase 2-beta (TOP2B).	[21]
ORG2058	DMH1M6N	Investigative	ORG2058 decreases the expression of DNA topoisomerase 2-beta (TOP2B).	[22]
1,4-Naphthoquinone	DMTCMH7	Investigative	1,4-Naphthoquinone affects the activity of DNA topoisomerase 2-beta (TOP2B).	[21]
1,2-NAPHTHOQUINONE	DMYXELH	Investigative	1,2-NAPHTHOQUINONE affects the activity of DNA topoisomerase 2-beta (TOP2B).	[21]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of DNA topoisomerase 2-beta (TOP2B).	[16]

References

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• [11] Chlorpyrifos Induces MLL Translocations Through Caspase 3-Dependent Genomic Instability and Topoisomerase II Inhibition in Human Fetal Liver Hematopoietic Stem Cells. Toxicol Sci. 2015 Oct;147(2):588-606. doi: 10.1093/toxsci/kfv153. Epub 2015 Jul 20.
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• [14] Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
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• [17] 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.
• [18] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [19] 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.
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• [21] 1,2-Naphthoquinone as a Poison of Human Type II Topoisomerases. Chem Res Toxicol. 2021 Apr 19;34(4):1082-1090. doi: 10.1021/acs.chemrestox.0c00492. Epub 2021 Mar 24.
• [22] The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5. Mol Endocrinol. 2010 Jul;24(7):1380-92. doi: 10.1210/me.2009-0516. Epub 2010 Jun 2.
• [23] Mutation P732L in human DNA topoisomerase IIbeta abolishes DNA cleavage in the presence of calcium and confers drug resistance. Mol Pharmacol. 2006 Jan;69(1):130-9. doi: 10.1124/mol.105.015933. Epub 2005 Oct 20.
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• [25] Mutation E522K in human DNA topoisomerase IIbeta confers resistance to methyl N-(4'-(9-acridinylamino)-phenyl)carbamate hydrochloride and methyl N-(4'-(9-acridinylamino)-3-methoxy-phenyl) methane sulfonamide but hypersensitivity to etoposide. Mol Pharmacol. 2004 Sep;66(3):430-9. doi: 10.1124/mol.66.3..