Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQIVY9B)

• DOT Name: Zinc finger and BTB domain-containing protein 7A
• Synonyms: Factor binding IST protein 1; FBI-1; Factor that binds to inducer of short transcripts protein 1; HIV-1 1st-binding protein 1; Leukemia/lymphoma-related factor; POZ and Krueppel erythroid myeloid ontogenic factor; POK erythroid myeloid ontogenic factor; Pokemon; Pokemon 1; TTF-I-interacting peptide 21; TIP21; Zinc finger protein 857A
• Gene Name: ZBTB7A
• Related Disease:
  Complex neurodevelopmental disorder
  Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin
• UniProt ID: ZBT7A_HUMAN
• PDB ID: 2IF5; 2NN2; 7EYI; 7N5S; 7N5T; 7N5U; 7N5V; 7N5W; 8E3D; 8E3E; 8H9H
• Pfam ID: PF00651 ; PF00096
• Sequence:
  MAGGVDGPIGIPFPDHSSDILSGLNEQRTQGLLCDVVILVEGREFPTHRSVLAACSQYFK
  KLFTSGAVVDQQNVYEIDFVSAEALTALMDFAYTATLTVSTANVGDILSAARLLEIPAVS
  HVCADLLDRQILAADAGADAGQLDLVDQIDQRNLLRAKEYLEFFQSNPMNSLPPAAAAAA
  ASFPWSAFGASDDDLDATKEAVAAAVAAVAAGDCNGLDFYGPGPPAERPPTGDGDEGDSN
  PGLWPERDEDAPTGGLFPPPVAPPAATQNGHYGRGGEEEAASLSEAAPEPGDSPGFLSGA
  AEGEDGDGPDVDGLAASTLLQQMMSSVGRAGAAAGDSDEESRADDKGVMDYYLKYFSGAH
  DGDVYPAWSQKVEKKIRAKAFQKCPICEKVIQGAGKLPRHIRTHTGEKPYECNICKVRFT
  RQDKLKVHMRKHTGEKPYLCQQCGAAFAHNYDLKNHMRVHTGLRPYQCDSCCKTFVRSDH
  LHRHLKKDGCNGVPSRRGRKPRVRGGAPDPSPGATATPGAPAQPSSPDARRNGQEKHFKD
  EDEDEDVASPDGLGRLNVAGAGGGGDSGGGPGAATDGNFTAGLA
• Function: Transcription factor that represses the transcription of a wide range of genes involved in cell proliferation and differentiation. Directly and specifically binds to the consensus sequence 5'-[GA][CA]GACCCCCCCCC-3' and represses transcription both by regulating the organization of chromatin and through the direct recruitment of transcription factors to gene regulatory regions. Negatively regulates SMAD4 transcriptional activity in the TGF-beta signaling pathway through these two mechanisms. That is, recruits the chromatin regulator HDAC1 to the SMAD4-DNA complex and in parallel prevents the recruitment of the transcriptional activators CREBBP and EP300. Collaborates with transcription factors like RELA to modify the accessibility of gene transcription regulatory regions to secondary transcription factors. Also directly interacts with transcription factors like SP1 to prevent their binding to DNA. Functions as an androgen receptor/AR transcriptional corepressor by recruiting NCOR1 and NCOR2 to the androgen response elements/ARE on target genes. Thereby, negatively regulates androgen receptor signaling and androgen-induced cell proliferation. Involved in the switch between fetal and adult globin expression during erythroid cells maturation. Through its interaction with the NuRD complex regulates chromatin at the fetal globin genes to repress their transcription. Specifically represses the transcription of the tumor suppressor ARF isoform from the CDKN2A gene. Efficiently abrogates E2F1-dependent CDKN2A transactivation. Regulates chondrogenesis through the transcriptional repression of specific genes via a mechanism that also requires histone deacetylation. Regulates cell proliferation through the transcriptional regulation of genes involved in glycolysis. Involved in adipogenesis through the regulation of genes involved in adipocyte differentiation. Plays a key role in the differentiation of lymphoid progenitors into B and T lineages. Promotes differentiation towards the B lineage by inhibiting the T-cell instructive Notch signaling pathway through the specific transcriptional repression of Notch downstream target genes. Also regulates osteoclast differentiation. May also play a role, independently of its transcriptional activity, in double-strand break repair via classical non-homologous end joining/cNHEJ. Recruited to double-strand break sites on damage DNA, interacts with the DNA-dependent protein kinase complex and directly regulates its stability and activity in DNA repair. May also modulate the splicing activity of KHDRBS1 toward BCL2L1 in a mechanism which is histone deacetylase-dependent and thereby negatively regulates the pro-apoptotic effect of KHDRBS1.
• Tissue Specificity: Widely expressed . In normal thymus, expressed in medullary epithelial cells and Hassle's corpuscles (at protein level) . In tonsil, expressed in squamous epithelium and germinal center lymphocytes (at protein level) . Up-regulated in a subset of lymphomas, as well as in a subset of breast, lung, colon, prostate and bladder carcinomas (at protein level) . Expressed in adipose tissues .

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Strong	Autosomal dominant	[1]
Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin	DISIOGNI	Strong	Autosomal dominant	[2]

7 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 Zinc finger and BTB domain-containing protein 7A.	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Zinc finger and BTB domain-containing protein 7A.	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Zinc finger and BTB domain-containing protein 7A.	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Zinc finger and BTB domain-containing protein 7A.	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Zinc finger and BTB domain-containing protein 7A.	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Zinc finger and BTB domain-containing protein 7A.	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Zinc finger and BTB domain-containing protein 7A.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Zinc finger and BTB domain-containing protein 7A.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Zinc finger and BTB domain-containing protein 7A.	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Zinc finger and BTB domain-containing protein 7A.	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Zinc finger and BTB domain-containing protein 7A.	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Zinc finger and BTB domain-containing protein 7A.	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Zinc finger and BTB domain-containing protein 7A.	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Zinc finger and BTB domain-containing protein 7A.	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Zinc finger and BTB domain-containing protein 7A.	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Zinc finger and BTB domain-containing protein 7A.	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Zinc finger and BTB domain-containing protein 7A.	[15]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation. Nat Commun. 2016 Jun 2;7:11733. doi: 10.1038/ncomms11733.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [13] Resveratrol Represses Pokemon Expression in Human Glioma Cells. Mol Neurobiol. 2016 Mar;53(2):1266-1278. doi: 10.1007/s12035-014-9081-2. Epub 2015 Jan 27.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] 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.
• [18] 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.