Details of Drug Off-Target (DOT)

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

• DOT Name: RNA-binding protein FUS (FUS)
• Synonyms: 75 kDa DNA-pairing protein; Oncogene FUS; Oncogene TLS; POMp75; Translocated in liposarcoma protein
• Gene Name: FUS
• Related Disease:
  Amyotrophic lateral sclerosis
  Amyotrophic lateral sclerosis type 6
  Juvenile amyotrophic lateral sclerosis
  Tremor, hereditary essential, 4
• UniProt ID: FUS_HUMAN
• PDB ID: 2LA6; 2LCW; 4FDD; 4FQ3; 5W3N; 5XRR; 5XSG; 5YVG; 5YVH; 5YVI; 6BWZ; 6BXV; 6BZP; 6G99; 6GBM; 6KJ1; 6KJ2; 6KJ3; 6KJ4; 6SNJ; 6XFM; 7CYL; 7VQQ
• Pfam ID: PF00076 ; PF00641
• Sequence:
  MASNDYTQQATQSYGAYPTQPGQGYSQQSSQPYGQQSYSGYSQSTDTSGYGQSSYSSYGQ
  SQNTGYGTQSTPQGYGSTGGYGSSQSSQSSYGQQSSYPGYGQQPAPSSTSGSYGSSSQSS
  SYGQPQSGSYSQQPSYGGQQQSYGQQQSYNPPQGYGQQNQYNSSSGGGGGGGGGGNYGQD
  QSSMSSGGGSGGGYGNQDQSGGGGSGGYGQQDRGGRGRGGSGGGGGGGGGGYNRSSGGYE
  PRGRGGGRGGRGGMGGSDRGGFNKFGGPRDQGSRHDSEQDNSDNNTIFVQGLGENVTIES
  VADYFKQIGIIKTNKKTGQPMINLYTDRETGKLKGEATVSFDDPPSAKAAIDWFDGKEFS
  GNPIKVSFATRRADFNRGGGNGRGGRGRGGPMGRGGYGGGGSGGGGRGGFPSGGGGGGGQ
  QRAGDWKCPNPTCENMNFSWRNECNQCKAPKPDGPGGGPGGSHMGGNYGDDRRGGRGGYD
  RGGYRGRGGDRGGFRGGRGGGDRGGFGPGKMDSRGEHRQDRRERPY
• Function: DNA/RNA-binding protein that plays a role in various cellular processes such as transcription regulation, RNA splicing, RNA transport, DNA repair and damage response. Binds to nascent pre-mRNAs and acts as a molecular mediator between RNA polymerase II and U1 small nuclear ribonucleoprotein thereby coupling transcription and splicing. Binds also its own pre-mRNA and autoregulates its expression; this autoregulation mechanism is mediated by non-sense-mediated decay. Plays a role in DNA repair mechanisms by promoting D-loop formation and homologous recombination during DNA double-strand break repair. In neuronal cells, plays crucial roles in dendritic spine formation and stability, RNA transport, mRNA stability and synaptic homeostasis.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Spliceosome (hsa03040)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis	DISF7HVM	Definitive	Autosomal dominant	[1]
Amyotrophic lateral sclerosis type 6	DIS8ZMZ8	Definitive	Autosomal dominant	[2]
Juvenile amyotrophic lateral sclerosis	DISKDZC9	Supportive	Autosomal recessive	[3]
Tremor, hereditary essential, 4	DISWEAGF	Limited	Autosomal dominant	[4]

19 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 RNA-binding protein FUS (FUS).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of RNA-binding protein FUS (FUS).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RNA-binding protein FUS (FUS).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RNA-binding protein FUS (FUS).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of RNA-binding protein FUS (FUS).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA-binding protein FUS (FUS).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of RNA-binding protein FUS (FUS).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of RNA-binding protein FUS (FUS).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of RNA-binding protein FUS (FUS).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of RNA-binding protein FUS (FUS).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of RNA-binding protein FUS (FUS).	[14]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of RNA-binding protein FUS (FUS).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of RNA-binding protein FUS (FUS).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of RNA-binding protein FUS (FUS).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of RNA-binding protein FUS (FUS).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of RNA-binding protein FUS (FUS).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of RNA-binding protein FUS (FUS).	[20]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of RNA-binding protein FUS (FUS).	[21]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of RNA-binding protein FUS (FUS).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of RNA-binding protein FUS (FUS).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of RNA-binding protein FUS (FUS).	[18]

References

• [1] De novo FUS mutations in 2 Korean patients with sporadic amyotrophic lateral sclerosis. Neurobiol Aging. 2015 Mar;36(3):1604.e17-9. doi: 10.1016/j.neurobiolaging.2014.10.002. Epub 2014 Oct 13.
• [2] 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.
• [3] P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis. Neuromuscul Disord. 2012 Jan;22(1):73-5. doi: 10.1016/j.nmd.2011.08.003. Epub 2011 Sep 9.
• [4] 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.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [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] 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] 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.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] 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.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis. 2008 Apr;29(4):779-89.
• [16] 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.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [20] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [21] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.
• [22] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.