Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6G8YF3)

• DOT Name: Probable ATP-dependent RNA helicase DDX20 (DDX20)
• Synonyms: EC 3.6.1.15; EC 3.6.4.13; Component of gems 3; DEAD box protein 20; DEAD box protein DP 103; Gemin-3
• Gene Name: DDX20
• Related Disease:
  Glaucoma/ocular hypertension
  OPTN-related open angle glaucoma
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Motor neurone disease
  Myopathy
  Oropharyngeal squamous cell carcinoma
  Prostate cancer
  Prostate carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Amyotrophic lateral sclerosis
  Osteoarthritis
• UniProt ID: DDX20_HUMAN
• PDB ID: 2OXC; 3B7G
• EC Number: 3.6.1.15; 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MAAAFEASGALAAVATAMPAEHVAVQVPAPEPTPGPVRILRTAQDLSSPRTRTGDVLLAE
  PADFESLLLSRPVLEGLRAAGFERPSPVQLKAIPLGRCGLDLIVQAKSGTGKTCVFSTIA
  LDSLVLENLSTQILILAPTREIAVQIHSVITAIGIKMEGLECHVFIGGTPLSQDKTRLKK
  CHIAVGSPGRIKQLIELDYLNPGSIRLFILDEADKLLEEGSFQEQINWIYSSLPASKQML
  AVSATYPEFLANALTKYMRDPTFVRLNSSDPSLIGLKQYYKVVNSYPLAHKVFEEKTQHL
  QELFSRIPFNQALVFSNLHSRAQHLADILSSKGFPAECISGNMNQNQRLDAMAKLKHFHC
  RVLISTDLTSRGIDAEKVNLVVNLDVPLDWETYMHRIGRAGRFGTLGLTVTYCCRGEEEN
  MMMRIAQKCNINLLPLPDPIPSGLMEECVDWDVEVKAAVHTYGIASVPNQPLKKQIQKIE
  RTLQIQKAHGDHMASSRNNSVSGLSVKSKNNTKQKLPVKSHSECGIIEKATSPKELGCDR
  QSEEQMKNSVQTPVENSTNSQHQVKEALPVSLPQIPCLSSFKIHQPYTLTFAELVEDYEH
  YIKEGLEKPVEIIRHYTGPGDQTVNPQNGFVRNKVIEQRVPVLASSSQSGDSESDSDSYS
  SRTSSQSKGNKSYLEGSSDNQLKDSESTPVDDRISLEQPPNGSDTPNPEKYQESPGIQMK
  TRLKEGASQRAKQSRRNLPRRSSFRLQTEAQEDDWYDCHREIRLSFSDTYQDYEEYWRAY
  YRAWQEYYAAASHSYYWNAQRHPSWMAAYHMNTIYLQEMMHSNQ
• Function: The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs. Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP. To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A forming an intermediate. Binding of snRNA inside 5Sm triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP. May also play a role in the metabolism of small nucleolar ribonucleoprotein (snoRNPs).
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  SARS-CoV-2 modulates host translation machinery (R-HSA-9754678)
  snRNP Assembly (R-HSA-191859)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glaucoma/ocular hypertension	DISLBXBY	Definitive	Genetic Variation	[1]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Motor neurone disease	DISUHWUI	Strong	Biomarker	[7]
Myopathy	DISOWG27	Strong	Altered Expression	[8]
Oropharyngeal squamous cell carcinoma	DIS7D7QV	Strong	Genetic Variation	[9]
Prostate cancer	DISF190Y	Strong	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[6]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[3]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[10]
Osteoarthritis	DIS05URM	Limited	Altered Expression	[11]

11 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 Probable ATP-dependent RNA helicase DDX20 (DDX20).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[23]

3 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 affects the phosphorylation of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[20]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Probable ATP-dependent RNA helicase DDX20 (DDX20).	[24]

References

• [1] Analysis of the polymorphic variants of RAN and GEMIN3 genes and risk of Primary Open-Angle Glaucoma in the Polish population.Ophthalmic Genet. 2018 Apr;39(2):180-188. doi: 10.1080/13816810.2017.1381978. Epub 2017 Nov 2.
• [2] The multiple lives of DEAD-box RNA helicase DP103/DDX20/Gemin3.Biochem Soc Trans. 2018 Apr 17;46(2):329-341. doi: 10.1042/BST20180016. Epub 2018 Mar 9.
• [3] Evaluation of genetic variants in microRNA-related genes and risk of bladder cancer.Cancer Res. 2008 Apr 1;68(7):2530-7. doi: 10.1158/0008-5472.CAN-07-5991.
• [4] SMARCAD1 knockdown uncovers its role in breast cancer cell migration, invasion, and metastasis.Expert Opin Ther Targets. 2016 Sep;20(9):1035-43. doi: 10.1080/14728222.2016.1195059. Epub 2016 Jun 13.
• [5] Genetic polymorphisms of microRNA machinery genes predict overall survival of esophageal squamous carcinoma.J Clin Lab Anal. 2018 Jan;32(1):e22170. doi: 10.1002/jcla.22170. Epub 2017 Dec 11.
• [6] High expression of DDX20 enhances the proliferation and metastatic potential of prostate cancer cells through the NF-B pathway.Int J Mol Med. 2016 Jun;37(6):1551-7. doi: 10.3892/ijmm.2016.2575. Epub 2016 Apr 25.
• [7] Abnormal interaction of motor neuropathy-associated mutant HspB8 (Hsp22) forms with the RNA helicase Ddx20 (gemin3).Cell Stress Chaperones. 2010 Sep;15(5):567-82. doi: 10.1007/s12192-010-0169-y. Epub 2010 Feb 17.
• [8] Scurfy Mice Develop Features of Connective Tissue Disease Overlap Syndrome and Mixed Connective Tissue Disease in the Absence of Regulatory T Cells.Front Immunol. 2019 Apr 24;10:881. doi: 10.3389/fimmu.2019.00881. eCollection 2019.
• [9] Significance of microRNA-related variants in susceptibility to recurrence of oropharyngeal cancer patients after definitive radiotherapy.Oncotarget. 2016 Jun 7;7(23):35015-25. doi: 10.18632/oncotarget.9014.
• [10] SMN complex member Gemin3 self-interacts and has a functional relationship with ALS-linked proteins TDP-43, FUS and Sod1.Sci Rep. 2019 Dec 10;9(1):18666. doi: 10.1038/s41598-019-53508-4.
• [11] Integrating transcriptome-wide study and mRNA expression profiles yields novel insights into the biological mechanism of chondropathies.Arthritis Res Ther. 2019 Aug 27;21(1):194. doi: 10.1186/s13075-019-1978-8.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [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] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.