Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFM8D3O)

• DOT Name: Transcriptional repressor p66-alpha (GATAD2A)
• Synonyms: Hp66alpha; GATA zinc finger domain-containing protein 2A
• Gene Name: GATAD2A
• Related Disease:
  Non-insulin dependent diabetes
  Thyroid gland papillary carcinoma
  Breast carcinoma
  Non-alcoholic fatty liver disease
  Schizophrenia
  Neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: P66A_HUMAN
• PDB ID: 2L2L
• Pfam ID: PF00320 ; PF16563
• Sequence:
  MTEEACRTRSQKRALERDPTEDDVESKKIKMERGLLASDLNTDGDMRVTPEPGAGPTQGL
  LRATEATAMAMGRGEGLVGDGPVDMRTSHSDMKSERRPPSPDVIVLSDNEQPSSPRVNGL
  TTVALKETSTEALMKSSPEERERMIKQLKEELRLEEAKLVLLKKLRQSQIQKEATAQKPT
  GSVGSTVTTPPPLVRGTQNIPAGKPSLQTSSARMPGSVIPPPLVRGGQQASSKLGPQASS
  QVVMPPLVRGAQQIHSIRQHSSTGPPPLLLAPRASVPSVQIQGQRIIQQGLIRVANVPNT
  SLLVNIPQPTPASLKGTTATSAQANSTPTSVASVVTSAESPASRQAAAKLALRKQLEKTL
  LEIPPPKPPAPEMNFLPSAANNEFIYLVGLEEVVQNLLETQGRMSAATVLSREPYMCAQC
  KTDFTCRWREEKSGAIMCENCMTTNQKKALKVEHTSRLKAAFVKALQQEQEIEQRLLQQG
  TAPAQAKAEPTAAPHPVLKQVIKPRRKLAFRSGEARDWSNGAVLQASSQLSRGSATTPRG
  VLHTFSPSPKLQNSASATALVSRTGRHSERTVSAGKGSATSNWKKTPLSTGGTLAFVSPS
  LAVHKSSSAVDRQREYLLDMIPPRSIPQSATWK
• Function: Transcriptional repressor. Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin. Enhances MBD2-mediated repression. Efficient repression requires the presence of GATAD2B.
• Tissue Specificity: Ubiquitous, both in fetal and adult tissues.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway:
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)
  Regulation of TP53 Activity through Acetylation (R-HSA-6804758)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Potential therapeutics for SARS (R-HSA-9679191)
  HDACs deacetylate histones (R-HSA-3214815)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Limited	Biomarker	[6]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[6]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[6]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Transcriptional repressor p66-alpha (GATAD2A).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcriptional repressor p66-alpha (GATAD2A).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcriptional repressor p66-alpha (GATAD2A).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcriptional repressor p66-alpha (GATAD2A).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcriptional repressor p66-alpha (GATAD2A).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcriptional repressor p66-alpha (GATAD2A).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcriptional repressor p66-alpha (GATAD2A).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Transcriptional repressor p66-alpha (GATAD2A).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transcriptional repressor p66-alpha (GATAD2A).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transcriptional repressor p66-alpha (GATAD2A).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcriptional repressor p66-alpha (GATAD2A).	[18]

4 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 Transcriptional repressor p66-alpha (GATAD2A).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Transcriptional repressor p66-alpha (GATAD2A).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcriptional repressor p66-alpha (GATAD2A).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Transcriptional repressor p66-alpha (GATAD2A).	[19]

References

• [1] Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease.Nat Genet. 2017 Oct;49(10):1450-1457. doi: 10.1038/ng.3943. Epub 2017 Sep 4.
• [2] Hsa_circ_0058124 promotes papillary thyroid cancer tumorigenesis and invasiveness through the NOTCH3/GATAD2A axis.J Exp Clin Cancer Res. 2019 Jul 19;38(1):318. doi: 10.1186/s13046-019-1321-x.
• [3] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [4] Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers.PLoS One. 2018 Jan 31;13(1):e0185490. doi: 10.1371/journal.pone.0185490. eCollection 2018.
• [5] Genes regulated by SATB2 during neurodevelopment contribute to schizophrenia and educational attainment.PLoS Genet. 2018 Jul 24;14(7):e1007515. doi: 10.1371/journal.pgen.1007515. eCollection 2018 Jul.
• [6] Knockdown of GATAD2A suppresses cell proliferation in thyroid cancer invitro.Oncol Rep. 2017 Apr;37(4):2147-2152. doi: 10.3892/or.2017.5436. Epub 2017 Feb 10.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [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] 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.
• [19] 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.
• [20] 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.