Details of Drug Off-Target (DOT)

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

• DOT Name: Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL)
• Synonyms: TOP6B like initiator of meiotic double strand breaks; Type 2 DNA topoisomerase VI subunit B-like; TOPOVIBL
• Gene Name: TOP6BL
• Related Disease: Hydatidiform mole, recurrent, 4
• UniProt ID: TO6BL_HUMAN
• Pfam ID: PF15091
• Sequence:
  MVLKKFLKEIQSILPGISAKLTWTSEEGSYSQDMTGVTPFQMIFEVDEKPRTLMTDCLVI
  KHFLRKIIMVHPKVRFHFSVKVNGILSTEIFGVENEPTLNLGNGIALLVDSQHYVSRPNF
  GTIESHCSRIHPVLGHPVMLFIPEDVAGMDLLGELILTPAAALCPSPKVSSNQLNRISSV
  SIFLYGPLGLPLILSTWEQPMTTFFKDTSSLVDWKKYHLCMIPNLDLNLDRDLVLPDVSY
  QVESSEEDQSQTMDPQGQTLLLFLFVDFHSAFPVQQMEIWGVYTLLTTHLNAILVESHSV
  VQGSIQFTVDKVLEQHHQAAKAQQKLQASLSVAVNSIMSILTGSTRSSFRKMCLQTLQAA
  DTQEFRTKLHKVFREITQHQFLHHCSCEVKQLTLEKKDSAQGTEDAPDNSSLELLADTSG
  QAENKRLKRGSPRIEEMRALRSARAPSPSEAAPRRPEATAAPLTPRGREHREAHGRALAP
  GRASLGSRLEDVLWLQEVSNLSEWLSPSPGP
• Function: [Isoform 3]: Component of a topoisomerase 6 complex specifically required for meiotic recombination. Together with SPO11, mediates DNA cleavage that forms the double-strand breaks (DSB) that initiate meiotic recombination. The complex promotes relaxation of negative and positive supercoiled DNA and DNA decatenation through cleavage and ligation cycles.
• Tissue Specificity: Detected in lung, spleen,colon and in skeletal muscle. Expressed in the ovaries, Fallopian tubes and uterus .

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hydatidiform mole, recurrent, 4	DIS5Z1PV	Limited	Autosomal recessive	[1]

10 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 Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL).	[4]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL).	[4]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL).	[5]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Type 2 DNA topoisomerase 6 subunit B-like (TOP6BL).	[8]

References

• [1] The TopoVIB-Like protein family is required for meiotic DNA double-strand break formation. Science. 2016 Feb 26;351(6276):943-9. doi: 10.1126/science.aad5309.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [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] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [11] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.