Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYO4VOX)

• DOT Name: Transcriptional repressor protein YY1
• Synonyms: Delta transcription factor; INO80 complex subunit S; NF-E1; Yin and yang 1; YY-1
• Gene Name: YY1
• Related Disease:
  Intellectual disability, autosomal dominant 40
  Gabriele de Vries syndrome
• UniProt ID: TYY1_HUMAN
• PDB ID: 1UBD; 1ZNM; 4C5I
• Pfam ID: PF00096
• Sequence:
  MASGDTLYIATDGSEMPAEIVELHEIEVETIPVETIETTVVGEEEEEDDDDEDGGGGDHG
  GGGGHGHAGHHHHHHHHHHHPPMIALQPLVTDDPTQVHHHQEVILVQTREEVVGGDDSDG
  LRAEDGFEDQILIPVPAPAGGDDDYIEQTLVTVAAAGKSGGGGSSSSGGGRVKKGGGKKS
  GKKSYLSGGAGAAGGGGADPGNKKWEQKQVQIKTLEGEFSVTMWSSDEKKDIDHETVVEE
  QIIGENSPPDYSEYMTGKKLPPGGIPGIDLSDPKQLAEFARMKPRKIKEDDAPRTIACPH
  KGCTKMFRDNSAMRKHLHTHGPRVHVCAECGKAFVESSKLKRHQLVHTGEKPFQCTFEGC
  GKRFSLDFNLRTHVRIHTGDRPYVCPFDGCNKKFAQSTNLKSHILTHAKAKNNQ
• Function: Multifunctional transcription factor that exhibits positive and negative control on a large number of cellular and viral genes by binding to sites overlapping the transcription start site. Binds to the consensus sequence 5'-CCGCCATNTT-3'; some genes have been shown to contain a longer binding motif allowing enhanced binding; the initial CG dinucleotide can be methylated greatly reducing the binding affinity. The effect on transcription regulation is depending upon the context in which it binds and diverse mechanisms of action include direct activation or repression, indirect activation or repression via cofactor recruitment, or activation or repression by disruption of binding sites or conformational DNA changes. Its activity is regulated by transcription factors and cytoplasmic proteins that have been shown to abrogate or completely inhibit YY1-mediated activation or repression. For example, it acts as a repressor in absence of adenovirus E1A protein but as an activator in its presence. Acts synergistically with the SMAD1 and SMAD4 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions. May play an important role in development and differentiation. Proposed to recruit the PRC2/EED-EZH2 complex to target genes that are transcriptional repressed. Involved in DNA repair. In vitro, binds to DNA recombination intermediate structures (Holliday junctions). Plays a role in regulating enhancer activation ; Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair; proposed to target the INO80 complex to YY1-responsive elements.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Polycomb repressive complex (hsa03083)
• Reactome Pathway:
  UCH proteinases (R-HSA-5689603)
  DNA Damage Recognition in GG-NER (R-HSA-5696394)
  TFAP2 (AP-2) family regulates transcription of growth factors and their receptors (R-HSA-8866910)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[1]
Gabriele de Vries syndrome	DISDW0C2	Strong	Autosomal dominant	[2]

1 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 Transcriptional repressor protein YY1.	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcriptional repressor protein YY1.	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transcriptional repressor protein YY1.	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transcriptional repressor protein YY1.	[6]
Artesunate	DMR27C8	Approved	Artesunate decreases the expression of Transcriptional repressor protein YY1.	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Transcriptional repressor protein YY1.	[8]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Transcriptional repressor protein YY1.	[9]
APR-246	DMNFADH	Phase 2	APR-246 increases the expression of Transcriptional repressor protein YY1.	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transcriptional repressor protein YY1.	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcriptional repressor protein YY1.	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transcriptional repressor protein YY1.	[9]
Bisindolylmaleimide-I	DMOQJZC	Investigative	Bisindolylmaleimide-I decreases the expression of Transcriptional repressor protein YY1.	[9]

References

• [1] A de novo paradigm for mental retardation. Nat Genet. 2010 Dec;42(12):1109-12. doi: 10.1038/ng.712. Epub 2010 Nov 14.
• [2] Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality. Mol Cell Biol. 1999 Oct;19(10):7237-44. doi: 10.1128/MCB.19.10.7237.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] YY1 is a novel potential therapeutic target for the treatment of HPV infection-induced cervical cancer by arsenic trioxide. Int J Gynecol Cancer. 2011 Aug;21(6):1097-104. doi: 10.1097/IGC.0b013e31821d2525.
• [6] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [7] Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate. Int J Oncol. 2009 Jul;35(1):149-58.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] Bisphenol A exposure disrupts aspartate transport in HepG2 cells. J Biochem Mol Toxicol. 2020 Aug;34(8):e22516. doi: 10.1002/jbt.22516. Epub 2020 May 3.
• [10] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [11] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [12] 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.