Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3U8FD0)

• DOT Name: ATP-dependent RNA helicase DDX1 (DDX1)
• Synonyms: EC 3.6.4.13; DEAD box protein 1; DEAD box protein retinoblastoma; DBP-RB
• Gene Name: DDX1
• Related Disease:
  Atypical endometrial hyperplasia
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Drug dependence
  Gastroenteritis
  Neoplasm
  Neoplasm of testis
  Neuroblastoma
  Ovarian neoplasm
  Retinoblastoma
  Seminoma
  Substance abuse
  Substance dependence
  Wilms tumor
  Advanced cancer
  Asthma
  Bloom syndrome
  Chronic obstructive pulmonary disease
  Hepatocellular carcinoma
• UniProt ID: DDX1_HUMAN
• PDB ID: 4XW3; 8TBX
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271 ; PF00622
• Sequence:
  MAAFSEMGVMPEIAQAVEEMDWLLPTDIQAESIPLILGGGDVLMAAETGSGKTGAFSIPV
  IQIVYETLKDQQEGKKGKTTIKTGASVLNKWQMNPYDRGSAFAIGSDGLCCQSREVKEWH
  GCRATKGLMKGKHYYEVSCHDQGLCRVGWSTMQASLDLGTDKFGFGFGGTGKKSHNKQFD
  NYGEEFTMHDTIGCYLDIDKGHVKFSKNGKDLGLAFEIPPHMKNQALFPACVLKNAELKF
  NFGEEEFKFPPKDGFVALSKAPDGYIVKSQHSGNAQVTQTKFLPNAPKALIVEPSRELAE
  QTLNNIKQFKKYIDNPKLRELLIIGGVAARDQLSVLENGVDIVVGTPGRLDDLVSTGKLN
  LSQVRFLVLDEADGLLSQGYSDFINRMHNQIPQVTSDGKRLQVIVCSATLHSFDVKKLSE
  KIMHFPTWVDLKGEDSVPDTVHHVVVPVNPKTDRLWERLGKSHIRTDDVHAKDNTRPGAN
  SPEMWSEAIKILKGEYAVRAIKEHKMDQAIIFCRTKIDCDNLEQYFIQQGGGPDKKGHQF
  SCVCLHGDRKPHERKQNLERFKKGDVRFLICTDVAARGIDIHGVPYVINVTLPDEKQNYV
  HRIGRVGRAERMGLAISLVATEKEKVWYHVCSSRGKGCYNTRLKEDGGCTIWYNEMQLLS
  EIEEHLNCTISQVEPDIKVPVDEFDGKVTYGQKRAAGGGSYKGHVDILAPTVQELAALEK
  EAQTSFLHLGYLPNQLFRTF
• Function: Acts as an ATP-dependent RNA helicase, able to unwind both RNA-RNA and RNA-DNA duplexes. Possesses 5' single-stranded RNA overhang nuclease activity. Possesses ATPase activity on various RNA, but not DNA polynucleotides. May play a role in RNA clearance at DNA double-strand breaks (DSBs), thereby facilitating the template-guided repair of transcriptionally active regions of the genome. Together with RELA, acts as a coactivator to enhance NF-kappa-B-mediated transcriptional activation. Acts as a positive transcriptional regulator of cyclin CCND2 expression. Binds to the cyclin CCND2 promoter region. Associates with chromatin at the NF-kappa-B promoter region via association with RELA. Binds to poly(A) RNA. May be involved in 3'-end cleavage and polyadenylation of pre-mRNAs. Component of the tRNA-splicing ligase complex required to facilitate the enzymatic turnover of catalytic subunit RTCB: together with archease (ZBTB8OS), acts by facilitating the guanylylation of RTCB, a key intermediate step in tRNA ligation. Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines via the adapter molecule TICAM1. Specifically binds (via helicase ATP-binding domain) on both short and long poly(I:C) dsRNA; (Microbial infection) Required for HIV-1 Rev function as well as for HIV-1 and coronavirus IBV replication. Binds to the RRE sequence of HIV-1 mRNAs; (Microbial infection) Required for Coronavirus IBV replication.
• Tissue Specificity: Highest levels of transcription in 2 retinoblastoma cell lines and in tissues of neuroectodermal origin including the retina, brain, and spinal cord.
• Reactome Pathway: tRNA processing in the nucleus (R-HSA-6784531)
• BioCyc Pathway: MetaCyc:ENSG00000079785-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atypical endometrial hyperplasia	DIS2POYG	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
Drug dependence	DIS9IXRC	Strong	Biomarker	[4]
Gastroenteritis	DISXQCG5	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Neoplasm of testis	DISK4XHT	Strong	Biomarker	[3]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[7]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[8]
Seminoma	DIS3J8LJ	Strong	Altered Expression	[9]
Substance abuse	DIS327VW	Strong	Biomarker	[4]
Substance dependence	DISDRAAR	Strong	Biomarker	[4]
Wilms tumor	DISB6T16	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[3]
Asthma	DISW9QNS	moderate	Biomarker	[11]
Bloom syndrome	DISKXQ7J	moderate	Biomarker	[12]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-dependent RNA helicase DDX1 (DDX1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-dependent RNA helicase DDX1 (DDX1).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of ATP-dependent RNA helicase DDX1 (DDX1).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of ATP-dependent RNA helicase DDX1 (DDX1).	[17]
Menadione	DMSJDTY	Approved	Menadione affects the expression of ATP-dependent RNA helicase DDX1 (DDX1).	[17]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of ATP-dependent RNA helicase DDX1 (DDX1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ATP-dependent RNA helicase DDX1 (DDX1).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ATP-dependent RNA helicase DDX1 (DDX1).	[23]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of ATP-dependent RNA helicase DDX1 (DDX1).	[24]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of ATP-dependent RNA helicase DDX1 (DDX1).	[25]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of ATP-dependent RNA helicase DDX1 (DDX1).	[19]

2 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 ATP-dependent RNA helicase DDX1 (DDX1).	[20]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of ATP-dependent RNA helicase DDX1 (DDX1).	[21]

References

• [1] Hormonally active doses of isoflavone aglycones promote mammary and endometrial carcinogenesis and alter the molecular tumor environment in Donryu rats.Toxicol Sci. 2012 Mar;126(1):39-51. doi: 10.1093/toxsci/kfs016. Epub 2012 Jan 16.
• [2] DEAD box 1 (DDX1) expression predicts for local control and overall survival in early stage, node-negative breast cancer.Cancer. 2012 Feb 15;118(4):888-98. doi: 10.1002/cncr.26352. Epub 2011 Jul 14.
• [3] DEAD box protein DDX1 promotes colorectal tumorigenesis through transcriptional activation of the LGR5 gene.Cancer Sci. 2018 Aug;109(8):2479-2489. doi: 10.1111/cas.13661. Epub 2018 Jul 17.
• [4] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [5] Cellular RNA Helicase DDX1 Is Involved in Transmissible Gastroenteritis Virus nsp14-Induced Interferon-Beta Production.Front Immunol. 2017 Aug 9;8:940. doi: 10.3389/fimmu.2017.00940. eCollection 2017.
• [6] Epigenetic down-regulated DDX10 promotes cell proliferation through Akt/NF-B pathway in ovarian cancer.Biochem Biophys Res Commun. 2016 Jan 22;469(4):1000-5. doi: 10.1016/j.bbrc.2015.12.069. Epub 2015 Dec 20.
• [7] The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression.Cell Rep. 2014 Sep 11;8(5):1447-60. doi: 10.1016/j.celrep.2014.07.058. Epub 2014 Aug 28.
• [8] Role of DEAD box 1 in retinoblastoma and neuroblastoma.Future Oncol. 2007 Oct;3(5):575-87. doi: 10.2217/14796694.3.5.575.
• [9] DDX1 is required for testicular tumorigenesis, partially through the transcriptional activation of 12p stem cell genes.Oncogene. 2009 May 28;28(21):2142-51. doi: 10.1038/onc.2009.89. Epub 2009 Apr 27.
• [10] Involvement of germline DDX1-MYCN duplication in inherited nephroblastoma.Eur J Med Genet. 2013 Dec;56(12):643-7. doi: 10.1016/j.ejmg.2013.10.004. Epub 2013 Oct 24.
• [11] Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis.Eur Respir J. 2014 Oct;44(4):860-72. doi: 10.1183/09031936.00001914. Epub 2014 Jul 3.
• [12] Role for RIF1-interacting partner DDX1 in BLM recruitment to DNA double-strand breaks.DNA Repair (Amst). 2017 Jul;55:47-63. doi: 10.1016/j.dnarep.2017.05.001. Epub 2017 May 13.
• [13] A Comprehensive Analysis of Argonaute-CLIP Data Identifies Novel, Conserved and Species-Specific Targets of miR-21 in Human Liver and Hepatocellular Carcinoma.Int J Mol Sci. 2018 Mar 14;19(3):851. doi: 10.3390/ijms19030851.
• [14] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [15] 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.
• [16] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [17] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [18] Protein profile in neuroblastoma cells incubated with S- and R-enantiomers of ibuprofen by iTRAQ-coupled 2-D LC-MS/MS analysis: possible action of induced proteins on Alzheimer's disease. Proteomics. 2008 Apr;8(8):1595-607. doi: 10.1002/pmic.200700556.
• [19] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [20] 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.
• [21] 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.
• [22] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [25] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.