Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLS124U)

• DOT Name: Probable ATP-dependent RNA helicase DDX5 (DDX5)
• Synonyms: EC 3.6.4.13; DEAD box protein 5; RNA helicase p68
• Gene Name: DDX5
• UniProt ID: DDX5_HUMAN
• PDB ID: 3FE2; 4A4D
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271 ; PF08061
• Sequence:
  MSGYSSDRDRGRDRGFGAPRFGGSRAGPLSGKKFGNPGEKLVKKKWNLDELPKFEKNFYQ
  EHPDLARRTAQEVETYRRSKEITVRGHNCPKPVLNFYEANFPANVMDVIARQNFTEPTAI
  QAQGWPVALSGLDMVGVAQTGSGKTLSYLLPAIVHINHQPFLERGDGPICLVLAPTRELA
  QQVQQVAAEYCRACRLKSTCIYGGAPKGPQIRDLERGVEICIATPGRLIDFLECGKTNLR
  RTTYLVLDEADRMLDMGFEPQIRKIVDQIRPDRQTLMWSATWPKEVRQLAEDFLKDYIHI
  NIGALELSANHNILQIVDVCHDVEKDEKLIRLMEEIMSEKENKTIVFVETKRRCDELTRK
  MRRDGWPAMGIHGDKSQQERDWVLNEFKHGKAPILIATDVASRGLDVEDVKFVINYDYPN
  SSEDYIHRIGRTARSTKTGTAYTFFTPNNIKQVSDLISVLREANQAINPKLLQLVEDRGS
  GRSRGRGGMKDDRRDRYSAGKRGGFNTFRDRENYDRGYSSLLKRDFGAKTQNGVYSAANY
  TNGSFGSNFVSAGIQTSFRTGNPTGTYQNGYDSTQQYGSNVPNMHNGMNQQAYAYPATAA
  APMIGYPMPTGYSQ
• Function: Involved in the alternative regulation of pre-mRNA splicing; its RNA helicase activity is necessary for increasing tau exon 10 inclusion and occurs in a RBM4-dependent manner. Binds to the tau pre-mRNA in the stem-loop region downstream of exon 10. The rate of ATP hydrolysis is highly stimulated by single-stranded RNA. Involved in transcriptional regulation; the function is independent of the RNA helicase activity. Transcriptional coactivator for androgen receptor AR but probably not ESR1. Synergizes with DDX17 and SRA1 RNA to activate MYOD1 transcriptional activity and involved in skeletal muscle differentiation. Transcriptional coactivator for p53/TP53 and involved in p53/TP53 transcriptional response to DNA damage and p53/TP53-dependent apoptosis. Transcriptional coactivator for RUNX2 and involved in regulation of osteoblast differentiation. Acts as a transcriptional repressor in a promoter-specific manner; the function probably involves association with histone deacetylases, such as HDAC1. As component of a large PER complex is involved in the inhibition of 3' transcriptional termination of circadian target genes such as PER1 and NR1D1 and the control of the circadian rhythms.
• KEGG Pathway:
  Spliceosome (hsa03040)
  Transcriptio.l misregulation in cancer (hsa05202)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Replication of the SARS-CoV-1 genome (R-HSA-9682706)
  Replication of the SARS-CoV-2 genome (R-HSA-9694686)
  SUMOylation of transcription cofactors (R-HSA-3899300)

Molecular Interaction Atlas (MIA) of This DOT

13 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 DDX5 (DDX5).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[7]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[8]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[7]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[13]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Probable ATP-dependent RNA helicase DDX5 (DDX5).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] 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.
• [4] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [5] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [6] 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.
• [7] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [8] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [9] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [10] 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.
• [11] 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.
• [12] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.