Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV73GMZ)

• DOT Name: Nucleolar RNA helicase 2 (DDX21)
• Synonyms: EC 3.6.4.13; DEAD box protein 21; Gu-alpha; Nucleolar RNA helicase Gu; Nucleolar RNA helicase II; RH II/Gu
• Gene Name: DDX21
• Related Disease:
  Neoplasm
  Breast cancer
  Breast carcinoma
  Cytomegalovirus infection
  Advanced cancer
  Diamond-Blackfan anemia
  Treacher-Collins syndrome
  Connective tissue disorder
  Gastric cancer
  Stomach cancer
• UniProt ID: DDX21_HUMAN
• PDB ID: 2M3D; 6L5L; 6L5M; 6L5N; 6L5O
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF08152 ; PF00271
• Sequence:
  MPGKLRSDAGLESDTAMKKGETLRKQTEEKEKKEKPKSDKTEEIAEEEETVFPKAKQVKK
  KAEPSEVDMNSPKSKKAKKKEEPSQNDISPKTKSLRKKKEPIEKKVVSSKTKKVTKNEEP
  SEEEIDAPKPKKMKKEKEMNGETREKSPKLKNGFPHPEPDCNPSEAASEESNSEIEQEIP
  VEQKEGAFSNFPISEETIKLLKGRGVTFLFPIQAKTFHHVYSGKDLIAQARTGTGKTFSF
  AIPLIEKLHGELQDRKRGRAPQVLVLAPTRELANQVSKDFSDITKKLSVACFYGGTPYGG
  QFERMRNGIDILVGTPGRIKDHIQNGKLDLTKLKHVVLDEVDQMLDMGFADQVEEILSVA
  YKKDSEDNPQTLLFSATCPHWVFNVAKKYMKSTYEQVDLIGKKTQKTAITVEHLAIKCHW
  TQRAAVIGDVIRVYSGHQGRTIIFCETKKEAQELSQNSAIKQDAQSLHGDIPQKQREITL
  KGFRNGSFGVLVATNVAARGLDIPEVDLVIQSSPPKDVESYIHRSGRTGRAGRTGVCICF
  YQHKEEYQLVQVEQKAGIKFKRIGVPSATEIIKASSKDAIRLLDSVPPTAISHFKQSAEK
  LIEEKGAVEALAAALAHISGATSVDQRSLINSNVGFVTMILQCSIEMPNISYAWKELKEQ
  LGEEIDSKVKGMVFLKGKLGVCFDVPTASVTEIQEKWHDSRRWQLSVATEQPELEGPREG
  YGGFRGQREGSRGFRGQRDGNRRFRGQREGSRGPRGQRSGGGNKSNRSQNKGQKRSFSKA
  FGQ
• Function: RNA helicase that acts as a sensor of the transcriptional status of both RNA polymerase (Pol) I and II: promotes ribosomal RNA (rRNA) processing and transcription from polymerase II (Pol II). Binds various RNAs, such as rRNAs, snoRNAs, 7SK and, at lower extent, mRNAs. In the nucleolus, localizes to rDNA locus, where it directly binds rRNAs and snoRNAs, and promotes rRNA transcription, processing and modification. Required for rRNA 2'-O-methylation, possibly by promoting the recruitment of late-acting snoRNAs SNORD56 and SNORD58 with pre-ribosomal complexes. In the nucleoplasm, binds 7SK RNA and is recruited to the promoters of Pol II-transcribed genes: acts by facilitating the release of P-TEFb from inhibitory 7SK snRNP in a manner that is dependent on its helicase activity, thereby promoting transcription of its target genes. Functions as a cofactor for JUN-activated transcription: required for phosphorylation of JUN at 'Ser-77'. Can unwind double-stranded RNA (helicase) and can fold or introduce a secondary structure to a single-stranded RNA (foldase). Together with SIRT7, required to prevent R-loop-associated DNA damage and transcription-associated genomic instability: deacetylation by SIRT7 activates the helicase activity, thereby overcoming R-loop-mediated stalling of RNA polymerases. Involved in rRNA processing. May bind to specific miRNA hairpins. 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.
• Reactome Pathway:
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  B-WICH complex positively regulates rRNA expression (R-HSA-5250924)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Cytomegalovirus infection	DISCEMGC	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[4]
Diamond-Blackfan anemia	DISI2SNW	moderate	Genetic Variation	[5]
Treacher-Collins syndrome	DIS2GXZ1	moderate	Biomarker	[5]
Connective tissue disorder	DISKXBS3	Limited	Biomarker	[6]
Gastric cancer	DISXGOUK	Limited	Biomarker	[7]
Stomach cancer	DISKIJSX	Limited	Biomarker	[7]

22 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 Nucleolar RNA helicase 2 (DDX21).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nucleolar RNA helicase 2 (DDX21).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nucleolar RNA helicase 2 (DDX21).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nucleolar RNA helicase 2 (DDX21).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[16]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[17]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[18]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[19]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Nucleolar RNA helicase 2 (DDX21).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Nucleolar RNA helicase 2 (DDX21).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nucleolar RNA helicase 2 (DDX21).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Nucleolar RNA helicase 2 (DDX21).	[26]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[27]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Nucleolar RNA helicase 2 (DDX21).	[28]

3 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 decreases the sumoylation of Nucleolar RNA helicase 2 (DDX21).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Nucleolar RNA helicase 2 (DDX21).	[25]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Nucleolar RNA helicase 2 (DDX21).	[25]

References

• [1] Elevated DDX21 regulates c-Jun activity and rRNA processing in human breast cancers.Breast Cancer Res. 2014 Sep 28;16(5):449. doi: 10.1186/s13058-014-0449-z.
• [2] A double-negative feedback loop between DEAD-box protein DDX21 and Snail regulates epithelial-mesenchymal transition and metastasis in breast cancer.Cancer Lett. 2018 Nov 28;437:67-78. doi: 10.1016/j.canlet.2018.08.021. Epub 2018 Aug 27.
• [3] Dissecting the Role of DDX21 in Regulating Human Cytomegalovirus Replication.J Virol. 2019 Nov 26;93(24):e01222-19. doi: 10.1128/JVI.01222-19. Print 2019 Dec 15.
• [4] Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21.Mol Cell. 2019 Sep 19;75(6):1270-1285.e14. doi: 10.1016/j.molcel.2019.06.020. Epub 2019 Jul 24.
• [5] Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders.Nature. 2018 Feb 1;554(7690):112-117. doi: 10.1038/nature25449. Epub 2018 Jan 24.
• [6] Unique epitopes in RNA helicase II/Gu protein recognized by serum from a watermelon stomach patient.Mol Immunol. 2000 May;37(7):351-9. doi: 10.1016/s0161-5890(00)00062-6.
• [7] DDX21 promotes gastric cancer proliferation by regulating cell cycle.Biochem Biophys Res Commun. 2018 Nov 10;505(4):1189-1194. doi: 10.1016/j.bbrc.2018.10.060. Epub 2018 Oct 12.
• [8] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [9] 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.
• [10] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [13] 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.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [16] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Gene expression-signature of belinostat in cell lines is specific for histone deacetylase inhibitor treatment, with a corresponding signature in xenografts. Anticancer Drugs. 2009 Sep;20(8):682-92.
• [19] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [20] Gene expression profiling in Caco-2 human colon cells exposed to TCDD, benzo[a]pyrene, and natural Ah receptor agonists from cruciferous vegetables and citrus fruits. Toxicol In Vitro. 2008 Mar;22(2):396-410.
• [21] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] 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.
• [26] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [27] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [28] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.