Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTVSEY0)

• DOT Name: Endoribonuclease Dicer (DICER1)
• Synonyms: EC 3.1.26.3; Helicase with RNase motif; Helicase MOI
• Gene Name: DICER1
• Related Disease:
  DICER1-related tumor predisposition
  Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors
  Pleuropulmonary blastoma
  Obsolete DICER1 syndrome
  Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome
• UniProt ID: DICER_HUMAN
• PDB ID: 2EB1; 4NGB; 4NGC; 4NGD; 4NGF; 4NGG; 4NH3; 4NH5; 4NH6; 4NHA; 4WYQ; 5ZAK; 5ZAL; 5ZAM; 7XW2; 7XW3
• EC Number: 3.1.26.3
• Pfam ID: PF03368 ; PF20932 ; PF20930 ; PF20931 ; PF00271 ; PF02170 ; PF04851 ; PF00636
• Sequence:
  MKSPALQPLSMAGLQLMTPASSPMGPFFGLPWQQEAIHDNIYTPRKYQVELLEAALDHNT
  IVCLNTGSGKTFIAVLLTKELSYQIRGDFSRNGKRTVFLVNSANQVAQQVSAVRTHSDLK
  VGEYSNLEVNASWTKERWNQEFTKHQVLIMTCYVALNVLKNGYLSLSDINLLVFDECHLA
  ILDHPYREIMKLCENCPSCPRILGLTASILNGKCDPEELEEKIQKLEKILKSNAETATDL
  VVLDRYTSQPCEIVVDCGPFTDRSGLYERLLMELEEALNFINDCNISVHSKERDSTLISK
  QILSDCRAVLVVLGPWCADKVAGMMVRELQKYIKHEQEELHRKFLLFTDTFLRKIHALCE
  EHFSPASLDLKFVTPKVIKLLEILRKYKPYERQQFESVEWYNNRNQDNYVSWSDSEDDDE
  DEEIEEKEKPETNFPSPFTNILCGIIFVERRYTAVVLNRLIKEAGKQDPELAYISSNFIT
  GHGIGKNQPRNKQMEAEFRKQEEVLRKFRAHETNLLIATSIVEEGVDIPKCNLVVRFDLP
  TEYRSYVQSKGRARAPISNYIMLADTDKIKSFEEDLKTYKAIEKILRNKCSKSVDTGETD
  IDPVMDDDDVFPPYVLRPDDGGPRVTINTAIGHINRYCARLPSDPFTHLAPKCRTRELPD
  GTFYSTLYLPINSPLRASIVGPPMSCVRLAERVVALICCEKLHKIGELDDHLMPVGKETV
  KYEEELDLHDEEETSVPGRPGSTKRRQCYPKAIPECLRDSYPRPDQPCYLYVIGMVLTTP
  LPDELNFRRRKLYPPEDTTRCFGILTAKPIPQIPHFPVYTRSGEVTISIELKKSGFMLSL
  QMLELITRLHQYIFSHILRLEKPALEFKPTDADSAYCVLPLNVVNDSSTLDIDFKFMEDI
  EKSEARIGIPSTKYTKETPFVFKLEDYQDAVIIPRYRNFDQPHRFYVADVYTDLTPLSKF
  PSPEYETFAEYYKTKYNLDLTNLNQPLLDVDHTSSRLNLLTPRHLNQKGKALPLSSAEKR
  KAKWESLQNKQILVPELCAIHPIPASLWRKAVCLPSILYRLHCLLTAEELRAQTASDAGV
  GVRSLPADFRYPNLDFGWKKSIDSKSFISISNSSSAENDNYCKHSTIVPENAAHQGANRT
  SSLENHDQMSVNCRTLLSESPGKLHVEVSADLTAINGLSYNQNLANGSYDLANRDFCQGN
  QLNYYKQEIPVQPTTSYSIQNLYSYENQPQPSDECTLLSNKYLDGNANKSTSDGSPVMAV
  MPGTTDTIQVLKGRMDSEQSPSIGYSSRTLGPNPGLILQALTLSNASDGFNLERLEMLGD
  SFLKHAITTYLFCTYPDAHEGRLSYMRSKKVSNCNLYRLGKKKGLPSRMVVSIFDPPVNW
  LPPGYVVNQDKSNTDKWEKDEMTKDCMLANGKLDEDYEEEDEEEESLMWRAPKEEADYED
  DFLEYDQEHIRFIDNMLMGSGAFVKKISLSPFSTTDSAYEWKMPKKSSLGSMPFSSDFED
  FDYSSWDAMCYLDPSKAVEEDDFVVGFWNPSEENCGVDTGKQSISYDLHTEQCIADKSIA
  DCVEALLGCYLTSCGERAAQLFLCSLGLKVLPVIKRTDREKALCPTRENFNSQQKNLSVS
  CAAASVASSRSSVLKDSEYGCLKIPPRCMFDHPDADKTLNHLISGFENFEKKINYRFKNK
  AYLLQAFTHASYHYNTITDCYQRLEFLGDAILDYLITKHLYEDPRQHSPGVLTDLRSALV
  NNTIFASLAVKYDYHKYFKAVSPELFHVIDDFVQFQLEKNEMQGMDSELRRSEEDEEKEE
  DIEVPKAMGDIFESLAGAIYMDSGMSLETVWQVYYPMMRPLIEKFSANVPRSPVRELLEM
  EPETAKFSPAERTYDGKVRVTVEVVGKGKFKGVGRSYRIAKSAAARRALRSLKANQPQVP
  NS
• Function: Double-stranded RNA (dsRNA) endoribonuclease playing a central role in short dsRNA-mediated post-transcriptional gene silencing. Cleaves naturally occurring long dsRNAs and short hairpin pre-microRNAs (miRNA) into fragments of twenty-one to twenty-three nucleotides with 3' overhang of two nucleotides, producing respectively short interfering RNAs (siRNA) and mature microRNAs. SiRNAs and miRNAs serve as guide to direct the RNA-induced silencing complex (RISC) to complementary RNAs to degrade them or prevent their translation. Gene silencing mediated by siRNAs, also called RNA interference, controls the elimination of transcripts from mobile and repetitive DNA elements of the genome but also the degradation of exogenous RNA of viral origin for instance. The miRNA pathway on the other side is a mean to specifically regulate the expression of target genes.
• KEGG Pathway: MicroR.s in cancer (hsa05206)
• Reactome Pathway:
  Small interfering RNA (siRNA) biogenesis (R-HSA-426486)
  tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis (R-HSA-9708296)
  M-decay (R-HSA-9820841)
  MicroRNA (miRNA) biogenesis (R-HSA-203927)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
DICER1-related tumor predisposition	DISHCY33	Definitive	Autosomal dominant	[1]
Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors	DISVJILV	Definitive	Autosomal dominant	[2]
Pleuropulmonary blastoma	DIS3UCS9	Definitive	Autosomal dominant	[3]
Obsolete DICER1 syndrome	DIS8E66M	Supportive	Autosomal dominant	[4]
Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome	DISAL5LL	Limited	Unknown	[5]

3 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 Endoribonuclease Dicer (DICER1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Endoribonuclease Dicer (DICER1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Endoribonuclease Dicer (DICER1).	[21]

20 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 Endoribonuclease Dicer (DICER1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Endoribonuclease Dicer (DICER1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Endoribonuclease Dicer (DICER1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Endoribonuclease Dicer (DICER1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Endoribonuclease Dicer (DICER1).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Endoribonuclease Dicer (DICER1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Endoribonuclease Dicer (DICER1).	[13]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Endoribonuclease Dicer (DICER1).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Endoribonuclease Dicer (DICER1).	[16]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Endoribonuclease Dicer (DICER1).	[17]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Endoribonuclease Dicer (DICER1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Endoribonuclease Dicer (DICER1).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Endoribonuclease Dicer (DICER1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Endoribonuclease Dicer (DICER1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Endoribonuclease Dicer (DICER1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Endoribonuclease Dicer (DICER1).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Endoribonuclease Dicer (DICER1).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Endoribonuclease Dicer (DICER1).	[24]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Endoribonuclease Dicer (DICER1).	[25]
GSK343	DM9QU5Y	Investigative	GSK343 increases the expression of Endoribonuclease Dicer (DICER1).	[26]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Ovarian embryonal rhabdomyosarcoma is a rare manifestation of the DICER1 syndrome. Hum Pathol. 2015 Jun;46(6):917-22. doi: 10.1016/j.humpath.2015.02.008. Epub 2015 Mar 5.
• [3] Germline DICER1 mutations and familial cystic nephroma. J Med Genet. 2010 Dec;47(12):863-6. doi: 10.1136/jmg.2010.081216. Epub 2010 Oct 29.
• [4] DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet. 2011 Apr;48(4):273-8. doi: 10.1136/jmg.2010.083790. Epub 2011 Jan 25.
• [5] Expanding the phenotype of mutations in DICER1: mosaic missense mutations in the RNase IIIb domain of DICER1 cause GLOW syndrome. J Med Genet. 2014 May;51(5):294-302. doi: 10.1136/jmedgenet-2013-101943. Epub 2014 Mar 27.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] 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.
• [8] 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.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [17] miR-148a/LDLR mediates hypercholesterolemia induced by prenatal dexamethasone exposure in male offspring rats. Toxicol Appl Pharmacol. 2020 May 15;395:114979. doi: 10.1016/j.taap.2020.114979. Epub 2020 Mar 29.
• [18] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] 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.
• [22] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [25] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [26] Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER. Nat Commun. 2014 Oct 29;5:5203. doi: 10.1038/ncomms6203.