Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJBMS8T)

• DOT Name: Chromatin-remodeling ATPase INO80 (INO80)
• Synonyms: hINO80; EC 3.6.4.-; DNA helicase-related INO80 complex homolog 1; DNA helicase-related protein INO80; INO80 complex subunit A
• Gene Name: INO80
• Related Disease:
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Chromosomal disorder
  Colon cancer
  Colon carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Wilson disease
  Immunodeficiency, common variable, 1
  Chronic kidney disease
  Congenital heart disease
  Melanoma
• UniProt ID: INO80_HUMAN
• PDB ID: 6HTS; 7ZI4
• EC Number: 3.6.4.-
• Pfam ID: PF13892 ; PF00271 ; PF00176
• Sequence:
  MASELGARDDGGCTELAKPLYLQYLERALRLDHFLRQTSAIFNRNISSDDSEDGLDDSNP
  LLPQSGDPLIQVKEEPPNSLLGETSGAGSSGMLNTYSLNGVLQSESKCDKGNLYNFSKLK
  KSRKWLKSILLSDESSEADSQSEDDDEEELNLSREELHNMLRLHKYKKLHQNKYSKDKEL
  QQYQYYSAGLLSTYDPFYEQQRHLLGPKKKKFKEEKKLKAKLKKVKKKRRRDEELSSEES
  PRRHHHQTKVFAKFSHDAPPPGTKKKHLSIEQLNARRRKVWLSIVKKELPKANKQKASAR
  NLFLTNSRKLAHQCMKEVRRAALQAQKNCKETLPRARRLTKEMLLYWKKYEKVEKEHRKR
  AEKEALEQRKLDEEMREAKRQQRKLNFLITQTELYAHFMSRKRDMGHDGIQEEILRKLED
  SSTQRQIDIGGGVVVNITQEDYDSNHFKAQALKNAENAYHIHQARTRSFDEDAKESRAAA
  LRAANKSGTGFGESYSLANPSIRAGEDIPQPTIFNGKLKGYQLKGMNWLANLYEQGINGI
  LADEMGLGKTVQSIALLAHLAERENIWGPFLIISPASTLNNWHQEFTRFVPKFKVLPYWG
  NPHDRKVIRRFWSQKTLYTQDAPFHVVITSYQLVVQDVKYFQRVKWQYMVLDEAQALKSS
  SSVRWKILLQFQCRNRLLLTGTPIQNTMAELWALLHFIMPTLFDSHEEFNEWFSKDIESH
  AENKSAIDENQLSRLHMILKPFMLRRIKKDVENELSDKIEILMYCQLTSRQKLLYQALKN
  KISIEDLLQSSMGSTQQAQNTTSSLMNLVMQFRKVCNHPELFERQETWSPFHISLKPYHI
  SKFIYRHGQIRVFNHSRDRWLRVLSPFAPDYIQRSLFHRKGINEESCFSFLRFIDISPAE
  MANLMLQGLLARWLALFLSLKASYRLHQLRSWGAPEGESHQRYLRNKDFLLGVNFPLSFP
  NLCSCPLLKSLVFSSHCKAVSGYSDQVVHQRRSATSSLRRCLLTELPSFLCVASPRVTAV
  PLDSYCNDRSAEYERRVLKEGGSLAAKQCLLNGAPELAADWLNRRSQFFPEPAGGLWSIR
  PQNGWSFIRIPGKESLITDSGKLYALDVLLTRLKSQGHRVLIYSQMTRMIDLLEEYMVYR
  KHTYMRLDGSSKISERRDMVADFQNRNDIFVFLLSTRAGGLGINLTAADTVIFYDSDWNP
  TVDQQAMDRAHRLGQTKQVTVYRLICKGTIEERILQRAKEKSEIQRMVISGGNFKPDTLK
  PKEVVSLLLDDEELEKKLRLRQEEKRQQEETNRVKERKRKREKYAEKKKKEDELDGKRRK
  EGVNLVIPFVPSADNSNLSADGDDSFISVDSAMPSPFSEISISSELHTGSIPLDESSSDM
  LVIVDDPASSAPQSRATNSPASITGSVSDTVNGISIQEMPAAGRGHSARSRGRPKGSGST
  AKGAGKGRSRKSTAGSAAAMAGAKAGAAAASAAAYAAYGYNVSKGISASSPLQTSLVRPA
  GLADFGPSSASSPLSSPLSKGNNVPGNPKNLHMTSSLAPDSLVRKQGKGTNPSGGR
• Function: ATPase component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and DNA repair. Binds DNA. As part of the INO80 complex, remodels chromatin by shifting nucleosomes. Regulates transcription upon recruitment by YY1 to YY1-activated genes, where it acts as an essential coactivator. Involved in UV-damage excision DNA repair. The contribution to DNA double-strand break repair appears to be largely indirect through transcriptional regulation. Involved in DNA replication. Required for microtubule assembly during mitosis thereby regulating chromosome segregation cycle.
• Tissue Specificity: According to PubMed:10574462, widely expressed. According to PubMed:16298340, specifically expressed in brain, liver and pancreas.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway:
  DNA Damage Recognition in GG-NER (R-HSA-5696394)
  UCH proteinases (R-HSA-5689603)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Cervical cancer	DISFSHPF	Strong	Biomarker	[2]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[2]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[1]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Biomarker	[5]
Wilson disease	DISVS9H7	Strong	Genetic Variation	[6]
Immunodeficiency, common variable, 1	DIS4E6DF	Disputed	Autosomal recessive	[7]
Chronic kidney disease	DISW82R7	Limited	Genetic Variation	[8]
Congenital heart disease	DISQBA23	Limited	Genetic Variation	[9]
Melanoma	DIS1RRCY	Limited	Altered Expression	[10]

6 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 Chromatin-remodeling ATPase INO80 (INO80).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Chromatin-remodeling ATPase INO80 (INO80).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Chromatin-remodeling ATPase INO80 (INO80).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Chromatin-remodeling ATPase INO80 (INO80).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Chromatin-remodeling ATPase INO80 (INO80).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Chromatin-remodeling ATPase INO80 (INO80).	[18]

3 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 increases the methylation of Chromatin-remodeling ATPase INO80 (INO80).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Chromatin-remodeling ATPase INO80 (INO80).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Chromatin-remodeling ATPase INO80 (INO80).	[17]

References

• [1] INO80 is required for oncogenic transcription and tumor growth in non-small cell lung cancer.Oncogene. 2017 Mar;36(10):1430-1439. doi: 10.1038/onc.2016.311. Epub 2016 Sep 19.
• [2] Ino80 promotes cervical cancer tumorigenesis by activating Nanog expression.Oncotarget. 2016 Nov 1;7(44):72250-72262. doi: 10.18632/oncotarget.12667.
• [3] B Lymphoblastic Leukemia With a Novel t(11;15) (q23;q15) and Unique Burkittoid Morphologic and Immunophenotypic Findings in a 9-Year-Old Boy.Lab Med. 2015 Fall;46(4):320-6. doi: 10.1309/LM0BOC84GSQGHYKD.
• [4] INO80 haploinsufficiency inhibits colon cancer tumorigenesis via replication stress-induced apoptosis.Oncotarget. 2017 Dec 6;8(70):115041-115053. doi: 10.18632/oncotarget.22984. eCollection 2017 Dec 29.
• [5] miR-148a inhibits self-renewal of thyroid cancer stem cells via repressing INO80 expression.Oncol Rep. 2016 Dec;36(6):3387-3396. doi: 10.3892/or.2016.5203. Epub 2016 Oct 25.
• [6] Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype.Liver Int. 2019 Jan;39(1):177-186. doi: 10.1111/liv.13967. Epub 2018 Oct 8.
• [7] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [8] Genome-wide association and functional follow-up reveals new loci for kidney function.PLoS Genet. 2012;8(3):e1002584. doi: 10.1371/journal.pgen.1002584. Epub 2012 Mar 29.
• [9] Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease.Nat Commun. 2018 Jan 25;9(1):368. doi: 10.1038/s41467-017-02796-3.
• [10] INO80 governs superenhancer-mediated oncogenic transcription and tumor growth in melanoma.Genes Dev. 2016 Jun 15;30(12):1440-53. doi: 10.1101/gad.277178.115.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [15] 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.
• [16] 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.
• [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] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.