Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGURA53)

• DOT Name: Probable ATP-dependent RNA helicase DDX56 (DDX56)
• Synonyms: EC 3.6.4.13; ATP-dependent 61 kDa nucleolar RNA helicase; DEAD box protein 21; DEAD box protein 56
• Gene Name: DDX56
• Related Disease:
  Advanced cancer
  Glioblastoma multiforme
  Hepatitis
  Hepatitis A virus infection
  Hepatocellular carcinoma
  Meningitis
  Neoplasm of testis
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
  Visceral leishmaniasis
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Cryptococcosis
  Hepatitis C virus infection
  Neoplasm
• UniProt ID: DDX56_HUMAN
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MEDSEALGFEHMGLDPRLLQAVTDLGWSRPTLIQEKAIPLALEGKDLLARARTGSGKTAA
  YAIPMLQLLLHRKATGPVVEQAVRGLVLVPTKELARQAQSMIQQLATYCARDVRVANVSA
  AEDSVSQRAVLMEKPDVVVGTPSRILSHLQQDSLKLRDSLELLVVDEADLLFSFGFEEEL
  KSLLCHLPRIYQAFLMSATFNEDVQALKELILHNPVTLKLQESQLPGPDQLQQFQVVCET
  EEDKFLLLYALLKLSLIRGKSLLFVNTLERSYRLRLFLEQFSIPTCVLNGELPLRSRCHI
  ISQFNQGFYDCVIATDAEVLGAPVKGKRRGRGPKGDKASDPEAGVARGIDFHHVSAVLNF
  DLPPTPEAYIHRAGRTARANNPGIVLTFVLPTEQFHLGKIEELLSGENRGPILLPYQFRM
  EEIEGFRYRCRDAMRSVTKQAIREARLKEIKEELLHSEKLKTYFEDNPRDLQLLRHDLPL
  HPAVVKPHLGHVPDYLVPPALRGLVRPHKKRKKLSSSCRKAKRAKSQNPLRSFKHKGKKF
  RPTAKPS
• Function: Nucleolar RNA helicase that plays a role in various biological processes including innate immunity, ribosome biogenesis or nucleolus organization. Plays an essential role in maintaining nucleolar integrity in planarian stem cells. Maintains embryonic stem cells proliferation by conventional regulation of ribosome assembly and interaction with OCT4 and POU5F1 complex. Regulates antiviral innate immunity by inhibiting the virus-triggered signaling nuclear translocation of IRF3. Mechanistically, acts by disrupting the interaction between IRF3 and importin IPO5. May play a role in later stages of the processing of the pre-ribosomal particles leading to mature 60S ribosomal subunits. Has intrinsic ATPase activity; (Microbial infection) Helicase activity is important for packaging viral RNA into virions during West Nile virus infection; (Microbial infection) Plays a positive role in foot-and-mouth disease virus replication by inhibiting the phosphorylation of IRF3 leading to inhibition of type I interferon; (Microbial infection) Plays a positive role in EMCV replication by interrupting IRF3 phosphorylation and its nucleus translocation.
• Tissue Specificity: Detected in heart, brain, liver, pancreas, placenta and lung.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Hepatitis	DISXXX35	Strong	Biomarker	[3]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Meningitis	DISQABAA	Strong	Altered Expression	[4]
Neoplasm of testis	DISK4XHT	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[7]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[8]
Visceral leishmaniasis	DISTKEYK	moderate	Biomarker	[9]
B-cell neoplasm	DISVY326	Limited	Biomarker	[10]
Breast cancer	DIS7DPX1	Limited	Biomarker	[11]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[12]
Cryptococcosis	DISDYDTK	Limited	Altered Expression	[4]
Hepatitis C virus infection	DISQ0M8R	Limited	Genetic Variation	[13]
Neoplasm	DISZKGEW	Limited	Altered Expression	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Probable ATP-dependent RNA helicase DDX56 (DDX56).	[14]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Probable ATP-dependent RNA helicase DDX56 (DDX56).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Probable ATP-dependent RNA helicase DDX56 (DDX56).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Probable ATP-dependent RNA helicase DDX56 (DDX56).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Probable ATP-dependent RNA helicase DDX56 (DDX56).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Probable ATP-dependent RNA helicase DDX56 (DDX56).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable ATP-dependent RNA helicase DDX56 (DDX56).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Probable ATP-dependent RNA helicase DDX56 (DDX56).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Probable ATP-dependent RNA helicase DDX56 (DDX56).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Probable ATP-dependent RNA helicase DDX56 (DDX56).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Probable ATP-dependent RNA helicase DDX56 (DDX56).	[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 Probable ATP-dependent RNA helicase DDX56 (DDX56).	[21]

References

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• [2] Molecular characterization of DDX26, a human DEAD-box RNA helicase, located on chromosome 7p12.Braz J Med Biol Res. 2001 Oct;34(10):1237-45. doi: 10.1590/s0100-879x2001001000002.
• [3] DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control.Oncogene. 2006 Mar 30;25(14):1991-2003. doi: 10.1038/sj.onc.1209239.
• [4] Comparison of real-time florescence quantitative PCR measurements of VAD1 mRNA with three conventional methods in diagnosis and follow-up treatment of Cryptococcus neoformans infection.Mycoses. 2012 Jul;55(4):326-32. doi: 10.1111/j.1439-0507.2011.02100.x. Epub 2011 Sep 5.
• [5] 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.
• [6] The DEAD-box RNA helicase 51 controls non-small cell lung cancer proliferation by regulating cell cycle progression via multiple pathways.Sci Rep. 2016 May 20;6:26108. doi: 10.1038/srep26108.
• [7] p68/DdX5 supports -catenin & RNAP II during androgen receptor mediated transcription in prostate cancer.PLoS One. 2013;8(1):e54150. doi: 10.1371/journal.pone.0054150. Epub 2013 Jan 17.
• [8] Subsite-specific association of DEAD box RNA helicase DDX60 with the development and prognosis of oral squamous cell carcinoma.Oncotarget. 2016 Dec 20;7(51):85097-85108. doi: 10.18632/oncotarget.13197.
• [9] Evaluation of antileishmanial potential of computationally screened compounds targeting DEAD-box RNA helicase of Leishmania donovani.Int J Biol Macromol. 2019 Jan;121:480-487. doi: 10.1016/j.ijbiomac.2018.10.053. Epub 2018 Oct 13.
• [10] Oncogene RNA helicase DDX6 promotes the process of c-Myc expression in gastric cancer cells.Mol Carcinog. 2018 May;57(5):579-589. doi: 10.1002/mc.22781. Epub 2018 Jan 30.
• [11] The role of DEAD-box RNA helicase p68 (DDX5) in the development and treatment of breast cancer.J Cell Physiol. 2019 May;234(5):5478-5487. doi: 10.1002/jcp.26912. Epub 2018 Nov 11.
• [12] Oncogenic splicing abnormalities induced by DEAD-Box Helicase 56 amplification in colorectal cancer.Cancer Sci. 2019 Oct;110(10):3132-3144. doi: 10.1111/cas.14163. Epub 2019 Aug 29.
• [13] Cellular DEAD-box RNA helicase DDX6 modulates interaction of miR-122 with the 5' untranslated region of hepatitis C virus RNA.Virology. 2017 Jul;507:231-241. doi: 10.1016/j.virol.2017.04.014. Epub 2017 Apr 26.
• [14] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.