Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWY64L7)

• DOT Name: Ribonuclease T2 (RNASET2)
• Synonyms: EC 4.6.1.19; Ribonuclease 6
• Gene Name: RNASET2
• Related Disease:
  Brain disease
  Cystic leukoencephalopathy without megalencephaly
  Primary biliary cholangitis
  Aicardi-Goutieres syndrome
  Autoimmune disease
  Carcinoma
  Crohn disease
  Epilepsy
  Epithelial ovarian cancer
  Hyperthyroidism
  Inflammatory bowel disease
  Lung cancer
  Lung neoplasm
  Megalencephaly
  Melanoma
  Neuroendocrine cancer
  Ovarian cancer
  Ovarian neoplasm
  Advanced cancer
  Graves disease
  Intellectual disability
  Type-1 diabetes
  Leukodystrophy
  Vitiligo
• UniProt ID: RNT2_HUMAN
• PDB ID: 3T0O
• EC Number: 4.6.1.19
• Pfam ID: PF00445
• Sequence:
  MRPAALRGALLGCLCLALLCLGGADKRLRDNHEWKKLIMVQHWPETVCEKIQNDCRDPPD
  YWTIHGLWPDKSEGCNRSWPFNLEEIKDLLPEMRAYWPDVIHSFPNRSRFWKHEWEKHGT
  CAAQVDALNSQKKYFGRSLELYRELDLNSVLLKLGIKPSINYYQVADFKDALARVYGVIP
  KIQCLPPSQDEEVQTIGQIELCLTKQDQQLQNCTEPGEQPSPKQEVWLANGAAESRGLRV
  CEDGPVFYPPPKKTKH
• Function: Ribonuclease that plays an essential role in innate immune response by recognizing and degrading RNAs from microbial pathogens that are subsequently sensed by TLR8. Cleaves preferentially single-stranded RNA molecules between purine and uridine residues, which critically contributes to the supply of catabolic uridine and the generation of purine-2',3'-cyclophosphate-terminated oligoribonucleotides. In turn, RNase T2 degradation products promote the RNA-dependent activation of TLR8. Also plays a key role in degradation of mitochondrial RNA and processing of non-coding RNA imported from the cytosol into mitochondria. Participates as well in degradation of mitochondrion-associated cytosolic rRNAs.
• Tissue Specificity: Ubiquitous. Higher expression levels observed in the temporal lobe and fetal brain.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brain disease	DIS6ZC3X	Definitive	Biomarker	[1]
Cystic leukoencephalopathy without megalencephaly	DISSYSPD	Definitive	Autosomal recessive	[1]
Primary biliary cholangitis	DIS43E0O	Definitive	Genetic Variation	[2]
Aicardi-Goutieres syndrome	DIS1NH4X	Strong	Biomarker	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[5]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[6]
Epilepsy	DISBB28L	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Hyperthyroidism	DISX87ZH	Strong	Genetic Variation	[8]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung neoplasm	DISVARNB	Strong	Biomarker	[9]
Megalencephaly	DISYW5SV	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Biomarker	[10]
Neuroendocrine cancer	DISVGJET	Strong	Biomarker	[11]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[12]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[13]
Graves disease	DISU4KOQ	moderate	Genetic Variation	[8]
Intellectual disability	DISMBNXP	moderate	Biomarker	[14]
Type-1 diabetes	DIS7HLUB	Disputed	Genetic Variation	[15]
Leukodystrophy	DISVY1TT	Limited	Biomarker	[3]
Vitiligo	DISR05SL	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ribonuclease T2 (RNASET2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ribonuclease T2 (RNASET2).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Ribonuclease T2 (RNASET2).	[32]

13 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 Ribonuclease T2 (RNASET2).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ribonuclease T2 (RNASET2).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ribonuclease T2 (RNASET2).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ribonuclease T2 (RNASET2).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ribonuclease T2 (RNASET2).	[22]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ribonuclease T2 (RNASET2).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ribonuclease T2 (RNASET2).	[24]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Ribonuclease T2 (RNASET2).	[25]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Ribonuclease T2 (RNASET2).	[26]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Ribonuclease T2 (RNASET2).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Ribonuclease T2 (RNASET2).	[28]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Ribonuclease T2 (RNASET2).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ribonuclease T2 (RNASET2).	[31]

References

• [1] RNASET2-deficient cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection. Nat Genet. 2009 Jul;41(7):773-5. doi: 10.1038/ng.398. Epub 2009 Jun 14.
• [2] Genetic Risk Factors for Autoimmune Thyroid Disease might Affect the Susceptibility to and Modulate the Progression of Primary Biliary Cholangitis.J Gastrointestin Liver Dis. 2017 Sep;26(3):245-252. doi: 10.15403/jgld.2014.1121.263.kus.
• [3] RNASET2-deficient leukoencephalopathy mimicking congenital CMV infection and Aicardi-Goutieres syndrome: a case report with a novel pathogenic variant.Orphanet J Rare Dis. 2019 Jul 26;14(1):184. doi: 10.1186/s13023-019-1155-9.
• [4] Genetic risk variants for autoimmune diseases that influence gene expression in thymus.Hum Mol Genet. 2016 Jul 15;25(14):3117-3124. doi: 10.1093/hmg/ddw152. Epub 2016 May 19.
• [5] A Cell-Autonomous Oncosuppressive Role of Human RNASET2 Affecting ECM-Mediated Oncogenic Signaling.Cancers (Basel). 2019 Feb 22;11(2):255. doi: 10.3390/cancers11020255.
• [6] Association of Ribonuclease T2 Gene Polymorphisms With Decreased Expression and Clinical Characteristics of Severity inCrohn's Disease.Gastroenterology. 2017 Jul;153(1):219-232. doi: 10.1053/j.gastro.2017.04.002. Epub 2017 Apr 9.
• [7] RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory.Dis Model Mech. 2018 Jun 27;11(6):dmm032631. doi: 10.1242/dmm.032631.
• [8] RNASET2, GPR174, and PTPN22 gene polymorphisms are related to the risk of liver damage associated with the hyperthyroidism in patients with Graves' disease.J Clin Lab Anal. 2018 Feb;32(2):e22258. doi: 10.1002/jcla.22258. Epub 2017 May 31.
• [9] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [10] RNASET2 as a tumor antagonizing gene in a melanoma cancer model.Oncol Res. 2008;17(2):69-74. doi: 10.3727/096504008784523658.
• [11] New insights into hypoxia-related mechanisms involved in different microvascular patterns of bronchopulmonary carcinoids and poorly differentiated neuroendocrine carcinomas. Role of ribonuclease T2 (RNASET2) and HIF-1.Hum Pathol. 2018 Sep;79:66-76. doi: 10.1016/j.humpath.2018.04.028. Epub 2018 May 12.
• [12] Downregulation of tumor suppressor gene ribonuclease T2 and gametogenetin binding protein 2 is associated with drug resistance in ovarian cancer.Oncol Rep. 2014 Jul;32(1):362-72. doi: 10.3892/or.2014.3175. Epub 2014 May 13.
• [13] The human RNASET2 protein affects the polarization pattern of human macrophages in vitro.Immunol Lett. 2018 Nov;203:102-111. doi: 10.1016/j.imlet.2018.09.005. Epub 2018 Sep 12.
• [14] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [15] Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.J Autoimmun. 2018 May;89:90-100. doi: 10.1016/j.jaut.2017.12.008. Epub 2018 Jan 5.
• [16] Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.Nat Genet. 2016 Nov;48(11):1418-1424. doi: 10.1038/ng.3680. Epub 2016 Oct 10.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [22] 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.
• [23] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [24] 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.
• [25] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [26] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [27] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [28] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [29] 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.
• [30] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [31] 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.
• [32] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.