Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1QQ8H3)

• DOT Name: RISC-loading complex subunit TARBP2 (TARBP2)
• Synonyms: TAR RNA-binding protein 2; Trans-activation-responsive RNA-binding protein
• Gene Name: TARBP2
• Related Disease:
  Breast cancer
  Adenoma
  Adrenocortical carcinoma
  Alzheimer disease
  Astrocytoma
  Breast carcinoma
  Breast neoplasm
  Estrogen-receptor positive breast cancer
  Ewing sarcoma
  Hidradenitis suppurativa
  Huntington disease
  Immunodeficiency
  Laryngeal carcinoma
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Pleuropulmonary blastoma
  Precancerous condition
  Prostate cancer
  Skin cancer
  Transitional cell carcinoma
  Triple negative breast cancer
  Urothelial carcinoma
  Neoplasm
  Small lymphocytic lymphoma
  Advanced cancer
• UniProt ID: TRBP2_HUMAN
• PDB ID: 2CPN; 3ADL; 3LLH; 4WYQ; 5N8L; 5N8M; 5ZAK; 5ZAL; 5ZAM; 6ZBK
• Pfam ID: PF00035
• Sequence:
  MSEEEQGSGTTTGCGLPSIEQMLAANPGKTPISLLQEYGTRIGKTPVYDLLKAEGQAHQP
  NFTFRVTVGDTSCTGQGPSKKAAKHKAAEVALKHLKGGSMLEPALEDSSSFSPLDSSLPE
  DIPVFTAAAAATPVPSVVLTRSPPMELQPPVSPQQSECNPVGALQELVVQKGWRLPEYTV
  TQESGPAHRKEFTMTCRVERFIEIGSGTSKKLAKRNAAAKMLLRVHTVPLDARDGNEVEP
  DDDHFSIGVGSRLDGLRNRGPGCTWDSLRNSVGEKILSLRSCSLGSLGALGPACCRVLSE
  LSEEQAFHVSYLDIEELSLSGLCQCLVELSTQPATVCHGSATTREAARGEAARRALQYLK
  IMAGSK
• Function: Required for formation of the RNA induced silencing complex (RISC). Component of the RISC loading complex (RLC), also known as the micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, AGO2 and TARBP2. Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto AGO2. AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. May also play a role in the production of short interfering RNAs (siRNAs) from double-stranded RNA (dsRNA) by DICER1. Binds in vitro to the PRM1 3'-UTR. Seems to act as a repressor of translation. For some pre-miRNA substrates, may also alter the choice of cleavage site by DICER1. Negatively regulates IRF7-mediated IFN-beta signaling triggered by viral infection by inhibiting the phosphorylation of IRF7 and promoting its 'Lys'-48-linked ubiquitination and degradation ; (Microbial infection) Binds to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1, and stimulates translation of TAR-containing RNAs. This is achieved in part at least by binding to and inhibiting EIF2AK2/PKR, thereby reducing phosphorylation and inhibition of EIF2S1/eIF-2-alpha. May also promote translation of TAR-containing RNAs independently of EIF2AK2/PKR. Mediates recruitment of FTSJ3 methyltransferase to HIV-1 RNA, leading to 2'-O-methylation of the viral genome, allowing HIV-1 to escape the innate immune system.
• Reactome Pathway:
  Small interfering RNA (siRNA) biogenesis (R-HSA-426486)
  PKR-mediated signaling (R-HSA-9833482)
  MicroRNA (miRNA) biogenesis (R-HSA-203927)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[2]
Adrenocortical carcinoma	DISZF4HX	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Astrocytoma	DISL3V18	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[1]
Ewing sarcoma	DISQYLV3	Strong	Altered Expression	[7]
Hidradenitis suppurativa	DIS3ZNAK	Strong	Biomarker	[8]
Huntington disease	DISQPLA4	Strong	Biomarker	[6]
Immunodeficiency	DIS093I0	Strong	Biomarker	[9]
Laryngeal carcinoma	DISNHCIV	Strong	Genetic Variation	[10]
Lung cancer	DISCM4YA	Strong	Biomarker	[11]
Lung carcinoma	DISTR26C	Strong	Biomarker	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Pleuropulmonary blastoma	DIS3UCS9	Strong	Genetic Variation	[12]
Precancerous condition	DISV06FL	Strong	Biomarker	[13]
Prostate cancer	DISF190Y	Strong	Altered Expression	[14]
Skin cancer	DISTM18U	Strong	Biomarker	[13]
Transitional cell carcinoma	DISWVVDR	Strong	Genetic Variation	[15]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[16]
Urothelial carcinoma	DISRTNTN	Strong	Genetic Variation	[15]
Neoplasm	DISZKGEW	moderate	Biomarker	[11]
Small lymphocytic lymphoma	DIS30POX	moderate	Genetic Variation	[17]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of RISC-loading complex subunit TARBP2 (TARBP2).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RISC-loading complex subunit TARBP2 (TARBP2).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RISC-loading complex subunit TARBP2 (TARBP2).	[20]
Selenium	DM25CGV	Approved	Selenium increases the expression of RISC-loading complex subunit TARBP2 (TARBP2).	[21]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of RISC-loading complex subunit TARBP2 (TARBP2).	[22]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of RISC-loading complex subunit TARBP2 (TARBP2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of RISC-loading complex subunit TARBP2 (TARBP2).	[24]

2 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 RISC-loading complex subunit TARBP2 (TARBP2).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of RISC-loading complex subunit TARBP2 (TARBP2).	[23]

References

• [1] TARBP2-Enhanced Resistance during Tamoxifen Treatment in Breast Cancer.Cancers (Basel). 2019 Feb 12;11(2):210. doi: 10.3390/cancers11020210.
• [2] Low DICER1 expression is associated with poor clinical outcome in adrenocortical carcinoma.Oncotarget. 2015 Sep 8;6(26):22724-33. doi: 10.18632/oncotarget.4261.
• [3] Clinical and functional impact of TARBP2 over-expression in adrenocortical carcinoma.Endocr Relat Cancer. 2013 Jul 4;20(4):551-64. doi: 10.1530/ERC-13-0098. Print 2013 Aug.
• [4] SNP Variation in MicroRNA Biogenesis Pathway Genes as a New Innovation Strategy for Alzheimer Disease Diagnostics: A Study of 10 Candidate Genes in an Understudied Population From the Eastern Mediterranean.Alzheimer Dis Assoc Disord. 2016 Jul-Sep;30(3):203-9. doi: 10.1097/WAD.0000000000000135.
• [5] Cell-specific regulation of TRBP1 promoter by NF-Y transcription factor in lymphocytes and astrocytes.J Mol Biol. 2006 Feb 3;355(5):898-910. doi: 10.1016/j.jmb.2005.11.026. Epub 2005 Nov 28.
• [6] Metastasis-suppressor transcript destabilization through TARBP2 binding of mRNA hairpins.Nature. 2014 Sep 11;513(7517):256-60. doi: 10.1038/nature13466. Epub 2014 Jul 9.
• [7] A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic reagents in Ewing sarcoma.Cancer Cell. 2012 Jun 12;21(6):807-21. doi: 10.1016/j.ccr.2012.04.023.
• [8] The microRNA effector RNA-induced silencing complex in hidradenitis suppurativa: a significant dysregulation within active inflammatory lesions.Arch Dermatol Res. 2017 Sep;309(7):557-565. doi: 10.1007/s00403-017-1752-1. Epub 2017 Jun 20.
• [9] shRNAmediated silencing of TARBP2 inhibits NCIH1299 nonsmall cell lung cancer cell invasion and migration via the JNK/STAT3/AKT pathway.Mol Med Rep. 2016 Oct;14(4):3725-30. doi: 10.3892/mmr.2016.5723. Epub 2016 Sep 6.
• [10] Association of Polymorphic Variants of miRNA Processing Genes with Larynx Cancer Risk in a Polish Population.Biomed Res Int. 2015;2015:298378. doi: 10.1155/2015/298378. Epub 2015 Nov 25.
• [11] Nuclear TARBP2 Drives Oncogenic Dysregulation of RNA Splicing and Decay.Mol Cell. 2019 Sep 5;75(5):967-981.e9. doi: 10.1016/j.molcel.2019.06.001. Epub 2019 Jul 9.
• [12] A precursor microRNA in a cancer cell nucleus: get me out of here!.Cell Cycle. 2011 Mar 15;10(6):922-5. doi: 10.4161/cc.10.6.15119. Epub 2011 Mar 15.
• [13] Expression levels of the microRNA maturing microprocessor complex component DGCR8 and the RNA-induced silencing complex (RISC) components argonaute-1, argonaute-2, PACT, TARBP1, and TARBP2 in epithelial skin cancer.Mol Carcinog. 2012 Nov;51(11):916-22. doi: 10.1002/mc.20861. Epub 2011 Oct 24.
• [14] The activity and expression of microRNAs in prostate cancers.Mol Biosyst. 2010 Dec;6(12):2561-72. doi: 10.1039/c0mb00100g. Epub 2010 Oct 19.
• [15] Microsatellite instability and TARBP2 mutation study in upper urinary tract urothelial carcinoma.Am J Clin Pathol. 2013 Jun;139(6):765-70. doi: 10.1309/AJCPBSLP8XHSWLOW.
• [16] Up-regulation and worse prognostic marker of cytoplasmic TARBP2 expression in obstinate breast cancer.Med Oncol. 2014 Apr;31(4):868. doi: 10.1007/s12032-014-0868-9. Epub 2014 Feb 22.
• [17] Genetic variants in miRNA processing genes and pre-miRNAs are associated with the risk of chronic lymphocytic leukemia.PLoS One. 2015 Mar 20;10(3):e0118905. doi: 10.1371/journal.pone.0118905. eCollection 2015.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [23] 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.
• [24] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.