Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0Z6E1K)

• DOT Name: ATP-dependent RNA helicase DDX39A (DDX39A)
• Synonyms: EC 3.6.4.13; DEAD box protein 39; Nuclear RNA helicase URH49
• Gene Name: DDX39A
• Related Disease:
  Alzheimer disease
  Bladder cancer
  Cardiac disease
  Hepatitis C virus infection
  Neoplasm
  Nephritis
  Periodontal disease
  Periodontitis
  Prostate cancer
  Prostate carcinoma
  Psoriasis
  Rheumatoid arthritis
  Systemic lupus erythematosus
  Urinary bladder cancer
  Urinary bladder neoplasm
  Myocardial infarction
  Peripheral sensory neuropathies
  Type-1/2 diabetes
  Leprosy
  Advanced cancer
  Autoimmune disease
  Crohn disease
  Cystinuria
  Hematologic disease
  Hepatocellular carcinoma
  Myasthenia gravis
  Small lymphocytic lymphoma
  Type-1 diabetes
  Ulcerative colitis
• UniProt ID: DX39A_HUMAN
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MAEQDVENDLLDYDEEEEPQAPQESTPAPPKKDIKGSYVSIHSSGFRDFLLKPELLRAIV
  DCGFEHPSEVQHECIPQAILGMDVLCQAKSGMGKTAVFVLATLQQIEPVNGQVTVLVMCH
  TRELAFQISKEYERFSKYMPSVKVSVFFGGLSIKKDEEVLKKNCPHVVVGTPGRILALVR
  NRSFSLKNVKHFVLDECDKMLEQLDMRRDVQEIFRLTPHEKQCMMFSATLSKDIRPVCRK
  FMQDPMEVFVDDETKLTLHGLQQYYVKLKDSEKNRKLFDLLDVLEFNQVIIFVKSVQRCM
  ALAQLLVEQNFPAIAIHRGMAQEERLSRYQQFKDFQRRILVATNLFGRGMDIERVNIVFN
  YDMPEDSDTYLHRVARAGRFGTKGLAITFVSDENDAKILNDVQDRFEVNVAELPEEIDIS
  TYIEQSR
• Function: [Isoform 1]: Involved in pre-mRNA splicing. Required for the export of mRNA out of the nucleus.
• Tissue Specificity: Detected in testis, and at lower levels in brain, kidney, lung, thymus, spleen and salivary gland.
• Reactome Pathway:
  mRNA 3'-end processing (R-HSA-72187)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[3]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Nephritis	DISQZQ70	Strong	Genetic Variation	[5]
Periodontal disease	DISJQHVN	Strong	Biomarker	[6]
Periodontitis	DISI9JOI	Strong	Genetic Variation	[7]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[8]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[8]
Psoriasis	DIS59VMN	Strong	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[10]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[5]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Myocardial infarction	DIS655KI	moderate	Genetic Variation	[11]
Peripheral sensory neuropathies	DISYWI6M	moderate	Biomarker	[12]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[13]
Leprosy	DISAA4UI	Disputed	Biomarker	[14]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[15]
Autoimmune disease	DISORMTM	Limited	Genetic Variation	[16]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[17]
Cystinuria	DISCU7CO	Limited	Altered Expression	[18]
Hematologic disease	DIS9XD9A	Limited	Biomarker	[15]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[19]
Myasthenia gravis	DISELRCI	Limited	Genetic Variation	[16]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[15]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[20]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[17]

19 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 ATP-dependent RNA helicase DDX39A (DDX39A).	[21]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[27]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[28]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[29]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[29]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[30]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[32]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[33]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[34]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[35]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[36]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[39]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of ATP-dependent RNA helicase DDX39A (DDX39A).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of ATP-dependent RNA helicase DDX39A (DDX39A).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of ATP-dependent RNA helicase DDX39A (DDX39A).	[37]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of ATP-dependent RNA helicase DDX39A (DDX39A).	[38]

References

• [1] Association of alleles carried at TNFA -850 and BAT1 -22 with Alzheimer's disease.J Neuroinflammation. 2008 Aug 20;5:36. doi: 10.1186/1742-2094-5-36.
• [2] DDX39 acts as a suppressor of invasion for bladder cancer.Cancer Sci. 2012 Jul;103(7):1363-9. doi: 10.1111/j.1349-7006.2012.02298.x. Epub 2012 Jun 4.
• [3] Single nucleotide polymorphisms of cytokine-related genes and association with clinical outcome in a Chagas disease case-control study from Brazil.Mem Inst Oswaldo Cruz. 2018 May 14;113(6):e170489. doi: 10.1590/0074-02760170489.
• [4] The haplotype block, NFKBIL1-ATP6V1G2-BAT1-MICB-MICA, within the class III-class I boundary region of the human major histocompatibility complex may control susceptibility to hepatitis C virus-associated dilated cardiomyopathy.Tissue Antigens. 2005 Sep;66(3):200-8. doi: 10.1111/j.1399-0039.2005.00457.x.
• [5] Haplotype-specific gene expression profiles in a telomeric major histocompatibility complex gene cluster and susceptibility to autoimmune diseases.Genes Immun. 2006 Dec;7(8):625-31. doi: 10.1038/sj.gene.6364339. Epub 2006 Sep 14.
• [6] Salivary biomarkers in association with periodontal parameters and the periodontitis risk haplotype.Innate Immun. 2018 Oct;24(7):439-447. doi: 10.1177/1753425918796207. Epub 2018 Sep 3.
• [7] Genetic variation on the BAT1-NFKBIL1-LTA region of major histocompatibility complex class III associates with periodontitis. Infect Immun. 2014 May;82(5):1939-48.
• [8] The RNA helicase DDX39B and its paralog DDX39A regulate androgen receptor splice variant AR-V7 generation.Biochem Biophys Res Commun. 2017 Jan 29;483(1):271-276. doi: 10.1016/j.bbrc.2016.12.153. Epub 2016 Dec 23.
• [9] Polymorphic Variations Associated With Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients.Oncol Res. 2017 Sep 21;25(8):1223-1229. doi: 10.3727/096504017X14876245096439. Epub 2017 Mar 2.
• [10] BAT1 promoter polymorphism is associated with rheumatoid arthritis susceptibility.J Rheumatol. 2008 May;35(5):741-4. Epub 2008 Mar 15.
• [11] Association of variants in the BAT1-NFKBIL1-LTA genomic region with protection against myocardial infarction in Europeans.Hum Mol Genet. 2007 Aug 1;16(15):1821-7. doi: 10.1093/hmg/ddm130. Epub 2007 May 21.
• [12] Cytokine genotype suggests a role for inflammation in nucleoside analog-associated sensory neuropathy (NRTI-SN) and predicts an individual's NRTI-SN risk.AIDS Res Hum Retroviruses. 2008 Feb;24(2):117-23. doi: 10.1089/aid.2007.0168.
• [13] Alleles of the proximal promoter of BAT1, a putative anti-inflammatory gene adjacent to the TNF cluster, reduce transcription on a disease-associated MHC haplotype.Genes Cells. 2003 Apr;8(4):403-12. doi: 10.1046/j.1365-2443.2002.00641.x.
• [14] PARK2 and proinflammatory/anti-inflammatory cytokine gene interactions contribute to the susceptibility to leprosy: a case-control study of North Indian population.BMJ Open. 2014 Feb 27;4(2):e004239. doi: 10.1136/bmjopen-2013-004239.
• [15] Dual-action CXCR4-targeting liposomes in leukemia: function blocking and drug delivery.Blood Adv. 2019 Jul 23;3(14):2069-2081. doi: 10.1182/bloodadvances.2019000098.
• [16] Ancestral haplotypes carry haplotypic and haplospecific polymorphisms of BAT1: possible relevance to autoimmune disease.Eur J Immunogenet. 1992 Jun;19(3):121-7. doi: 10.1111/j.1744-313x.1992.tb00051.x.
• [17] Inflammatory bowel disease is linked to 19p13 and associated with ICAM-1.Inflamm Bowel Dis. 2004 May;10(3):173-81. doi: 10.1097/00054725-200405000-00001.
• [18] Human cystinuria-related transporter: localization and functional characterization.Kidney Int. 2001 May;59(5):1821-33. doi: 10.1046/j.1523-1755.2001.0590051821.x.
• [19] DDX39 promotes hepatocellular carcinoma growth and metastasis through activating Wnt/-catenin pathway.Cell Death Dis. 2018 Jun 4;9(6):675. doi: 10.1038/s41419-018-0591-0.
• [20] Polymorphisms at positions -22 and -348 in the promoter of the BAT1 gene affect transcription and the binding of nuclear factors.Hum Mol Genet. 2004 May 1;13(9):967-74. doi: 10.1093/hmg/ddh113. Epub 2004 Mar 17.
• [21] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] Nuclear proteome analysis of cisplatin-treated HeLa cells. Mutat Res. 2010 Sep 10;691(1-2):1-8. doi: 10.1016/j.mrfmmm.2010.06.002. Epub 2010 Jun 9.
• [27] 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.
• [28] 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.
• [29] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [30] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [31] 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.
• [32] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [33] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [34] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [35] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [36] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [37] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [38] 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.
• [39] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [40] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.