Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCE68KZ)

• DOT Name: Ribonuclease 3 (DROSHA)
• Synonyms: EC 3.1.26.3; Protein Drosha; Ribonuclease III; RNase III; p241
• Gene Name: DROSHA
• Related Disease:
  Primary cutaneous T-cell lymphoma
  Thyroid gland papillary carcinoma
  Adenoma
  Advanced cancer
  Alzheimer disease
  Bladder cancer
  Carcinoma
  Childhood kidney Wilms tumor
  Childhood myelodysplastic syndrome
  Classic Hodgkin lymphoma
  Colorectal carcinoma
  Dilated cardiomyopathy 1A
  Endometrial cancer
  Endometrial carcinoma
  Esophageal squamous cell carcinoma
  Essential hypertension
  Graves disease
  High blood pressure
  Huntington disease
  Leukemia
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Malignant peripheral nerve sheath tumor
  Malignant soft tissue neoplasm
  Myelodysplastic syndrome
  Neoplasm
  Non-small-cell lung cancer
  Ovarian neoplasm
  Pneumonia
  Pneumonitis
  Sarcoma
  Small lymphocytic lymphoma
  Squamous cell carcinoma
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Wilms tumor
  Breast cancer
  Breast carcinoma
  Cervical carcinoma
  Female hypogonadism
  Nasopharyngeal carcinoma
  Spinal muscular atrophy
  Adenocarcinoma
  Glomerulosclerosis
  Follicular lymphoma
  Male infertility
  Neoplasm of esophagus
  Temporal lobe epilepsy
• UniProt ID: RNC_HUMAN
• PDB ID: 2KHX; 2NA2; 5B16; 6LXD; 6LXE; 6V5B; 6V5C
• EC Number: 3.1.26.3
• Pfam ID: PF00035 ; PF14622 ; PF00636
• Sequence:
  MMQGNTCHRMSFHPGRGCPRGRGGHGARPSAPSFRPQNLRLLHPQQPPVQYQYEPPSAPS
  TTFSNSPAPNFLPPRPDFVPFPPPMPPSAQGPLPPCPIRPPFPNHQMRHPFPVPPCFPPM
  PPPMPCPNNPPVPGAPPGQGTFPFMMPPPSMPHPPPPPVMPQQVNYQYPPGYSHHNFPPP
  SFNSFQNNPSSFLPSANNSSSPHFRHLPPYPLPKAPSERRSPERLKHYDDHRHRDHSHGR
  GERHRSLDRRERGRSPDRRRQDSRYRSDYDRGRTPSRHRSYERSRERERERHRHRDNRRS
  PSLERSYKKEYKRSGRSYGLSVVPEPAGCTPELPGEIIKNTDSWAPPLEIVNHRSPSREK
  KRARWEEEKDRWSDNQSSGKDKNYTSIKEKEPEETMPDKNEEEEEELLKPVWIRCTHSEN
  YYSSDPMDQVGDSTVVGTSRLRDLYDKFEEELGSRQEKAKAARPPWEPPKTKLDEDLESS
  SESECESDEDSTCSSSSDSEVFDVIAEIKRKKAHPDRLHDELWYNDPGQMNDGPLCKCSA
  KARRTGIRHSIYPGEEAIKPCRPMTNNAGRLFHYRITVSPPTNFLTDRPTVIEYDDHEYI
  FEGFSMFAHAPLTNIPLCKVIRFNIDYTIHFIEEMMPENFCVKGLELFSLFLFRDILELY
  DWNLKGPLFEDSPPCCPRFHFMPRFVRFLPDGGKEVLSMHQILLYLLRCSKALVPEEEIA
  NMLQWEELEWQKYAEECKGMIVTNPGTKPSSVRIDQLDREQFNPDVITFPIIVHFGIRPA
  QLSYAGDPQYQKLWKSYVKLRHLLANSPKVKQTDKQKLAQREEALQKIRQKNTMRREVTV
  ELSSQGFWKTGIRSDVCQHAMMLPVLTHHIRYHQCLMHLDKLIGYTFQDRCLLQLAMTHP
  SHHLNFGMNPDHARNSLSNCGIRQPKYGDRKVHHMHMRKKGINTLINIMSRLGQDDPTPS
  RINHNERLEFLGDAVVEFLTSVHLYYLFPSLEEGGLATYRTAIVQNQHLAMLAKKLELDR
  FMLYAHGPDLCRESDLRHAMANCFEALIGAVYLEGSLEEAKQLFGRLLFNDPDLREVWLN
  YPLHPLQLQEPNTDRQLIETSPVLQKLTEFEEAIGVIFTHVRLLARAFTLRTVGFNHLTL
  GHNQRMEFLGDSIMQLVATEYLFIHFPDHHEGHLTLLRSSLVNNRTQAKVAEELGMQEYA
  ITNDKTKRPVALRTKTLADLLESFIAALYIDKDLEYVHTFMNVCFFPRLKEFILNQDWND
  PKSQLQQCCLTLRTEGKEPDIPLYKTLQTVGPSHARTYTVAVYFKGERIGCGKGPSIQQA
  EMGAAMDALEKYNFPQMAHQKRFIERKYRQELKEMRWEREHQEREPDETEDIKK
• Function: Ribonuclease III double-stranded (ds) RNA-specific endoribonuclease that is involved in the initial step of microRNA (miRNA) biogenesis. Component of the microprocessor complex that is required to process primary miRNA transcripts (pri-miRNAs) to release precursor miRNA (pre-miRNA) in the nucleus. Within the microprocessor complex, DROSHA cleaves the 3' and 5' strands of a stem-loop in pri-miRNAs (processing center 11 bp from the dsRNA-ssRNA junction) to release hairpin-shaped pre-miRNAs that are subsequently cut by the cytoplasmic DICER to generate mature miRNAs. Involved also in pre-rRNA processing. Cleaves double-strand RNA and does not cleave single-strand RNA. Involved in the formation of GW bodies.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Ribosome biogenesis in eukaryotes (hsa03008)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway: MicroRNA (miRNA) biogenesis (R-HSA-203927)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary cutaneous T-cell lymphoma	DIS35WVW	Definitive	Altered Expression	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Genetic Variation	[2]
Adenoma	DIS78ZEV	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[6]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Childhood kidney Wilms tumor	DIS0NMK3	Strong	Genetic Variation	[7]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Biomarker	[8]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Genetic Variation	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[10]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[11]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[12]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[13]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[14]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[9]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[15]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[9]
Leukemia	DISNAKFL	Strong	Altered Expression	[16]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[17]
Lung cancer	DISCM4YA	Strong	Biomarker	[18]
Lung carcinoma	DISTR26C	Strong	Biomarker	[18]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Genetic Variation	[19]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Genetic Variation	[20]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[18]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[21]
Pneumonia	DIS8EF3M	Strong	Biomarker	[22]
Pneumonitis	DIS88E0K	Strong	Biomarker	[22]
Sarcoma	DISZDG3U	Strong	Genetic Variation	[20]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[23]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[24]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[15]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[6]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[7]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[25]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[25]
Cervical carcinoma	DIST4S00	moderate	Altered Expression	[26]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[27]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[28]
Spinal muscular atrophy	DISTLKOB	moderate	Biomarker	[29]
Adenocarcinoma	DIS3IHTY	Disputed	Altered Expression	[30]
Glomerulosclerosis	DISJF20Z	Disputed	Genetic Variation	[7]
Follicular lymphoma	DISVEUR6	Limited	Altered Expression	[31]
Male infertility	DISY3YZZ	Limited	Biomarker	[32]
Neoplasm of esophagus	DISOLKAQ	Limited	Altered Expression	[33]
Temporal lobe epilepsy	DISNOPXX	Limited	Biomarker	[34]

7 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 Ribonuclease 3 (DROSHA).	[35]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ribonuclease 3 (DROSHA).	[36]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ribonuclease 3 (DROSHA).	[37]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ribonuclease 3 (DROSHA).	[38]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ribonuclease 3 (DROSHA).	[39]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ribonuclease 3 (DROSHA).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ribonuclease 3 (DROSHA).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ribonuclease 3 (DROSHA).	[40]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Ribonuclease 3 (DROSHA).	[42]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Ribonuclease 3 (DROSHA).	[44]

References

• [1] Low Drosha protein expression in cutaneous T-cell lymphoma is associated with worse disease outcome.J Eur Acad Dermatol Venereol. 2019 Sep;33(9):1695-1699. doi: 10.1111/jdv.15652. Epub 2019 Jun 6.
• [2] Association between Genetic Polymorphisms in microRNA Machinery Genes and Risk of Papillary Thyroid Carcinoma.Pathol Oncol Res. 2020 Apr;26(2):1235-1241. doi: 10.1007/s12253-019-00688-z. Epub 2019 Jun 27.
• [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] Using Pan RNA-Seq Analysis to Reveal the Ubiquitous Existence of 5' and 3' End Small RNAs.Front Genet. 2019 Feb 14;10:105. doi: 10.3389/fgene.2019.00105. eCollection 2019.
• [5] 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.
• [6] Genetic variation in DROSHA 3'UTR regulated by hsa-miR-27b is associated with bladder cancer risk.PLoS One. 2013 Nov 28;8(11):e81524. doi: 10.1371/journal.pone.0081524. eCollection 2013.
• [7] Loss or oncogenic mutation of DROSHA impairs kidney development and function, but is not sufficient for Wilms tumor formation.Int J Cancer. 2019 Mar 15;144(6):1391-1400. doi: 10.1002/ijc.31952. Epub 2018 Dec 3.
• [8] Impaired expression of DICER, DROSHA, SBDS and some microRNAs in mesenchymal stromal cells from myelodysplastic syndrome patients.Haematologica. 2012 Aug;97(8):1218-24. doi: 10.3324/haematol.2011.054437. Epub 2012 Feb 27.
• [9] DICER and DROSHA gene expression and polymorphisms in autoimmune thyroid diseases.Autoimmunity. 2016 Dec;49(8):514-522. doi: 10.1080/08916934.2016.1230846. Epub 2016 Nov 3.
• [10] miRNA biogenesis-associated RNase III nucleases Drosha and Dicer are upregulated in colorectal adenocarcinoma.Oncol Lett. 2017 Oct;14(4):4379-4383. doi: 10.3892/ol.2017.6674. Epub 2017 Jul 26.
• [11] Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure.Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2111-6. doi: 10.1073/pnas.0710228105. Epub 2008 Feb 6.
• [12] Major regulators of microRNAs biogenesis Dicer and Drosha are down-regulated in endometrial cancer.Tumour Biol. 2011 Aug;32(4):769-76. doi: 10.1007/s13277-011-0179-0. Epub 2011 May 11.
• [13] Relationship between altered expression levels of MIR21, MIR143, MIR145, and MIR205 and clinicopathologic features of esophageal squamous cell carcinoma.Dis Esophagus. 2011 Sep;24(7):523-30. doi: 10.1111/j.1442-2050.2011.01177.x. Epub 2011 Mar 31.
• [14] rs10719 Polymorphism Located within DROSHA 3'-Untranslated Region is Responsible for Development of Primary Hypertension by Disrupting Binding with microRNA-27b.Med Sci Monit. 2017 Feb 19;23:911-918. doi: 10.12659/msm.897607.
• [15] 3'-UTR Polymorphisms in the MiRNA Machinery Genes DROSHA, DICER1, RAN, and XPO5 Are Associated with Colorectal Cancer Risk in a Korean Population.PLoS One. 2015 Jul 6;10(7):e0131125. doi: 10.1371/journal.pone.0131125. eCollection 2015.
• [16] Oncogenic All1 fusion proteins target Drosha-mediated microRNA processing.Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):10980-5. doi: 10.1073/pnas.0704559104. Epub 2007 Jun 20.
• [17] Inherited polymorphisms in the RNA-mediated interference machinery affect microRNA expression and lung cancer survival.Br J Cancer. 2010 Dec 7;103(12):1870-4. doi: 10.1038/sj.bjc.6605976. Epub 2010 Nov 23.
• [18] High copy number variation of cancer-related microRNA genes and frequent amplification of DICER1 and DROSHA in lung cancer.Oncotarget. 2015 Sep 15;6(27):23399-416. doi: 10.18632/oncotarget.4351.
• [19] Common genetic variants in the microRNA biogenesis pathway are associated with malignant peripheral nerve sheath tumor risk in a Chinese population.Cancer Epidemiol. 2013 Dec;37(6):913-6. doi: 10.1016/j.canep.2013.05.003. Epub 2013 Jun 12.
• [20] Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma.Br J Cancer. 2017 Jun 6;116(12):1621-1626. doi: 10.1038/bjc.2017.147. Epub 2017 May 18.
• [21] Dicer, Drosha, and outcomes in patients with ovarian cancer.N Engl J Med. 2008 Dec 18;359(25):2641-50. doi: 10.1056/NEJMoa0803785.
• [22] DROSHA-Dependent AIM2 Inflammasome Activation Contributes to Lung Inflammation during Idiopathic Pulmonary Fibrosis.Cells. 2019 Aug 20;8(8):938. doi: 10.3390/cells8080938.
• [23] 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.
• [24] Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups.Nat Commun. 2013;4:2873. doi: 10.1038/ncomms3873.
• [25] Genetic variants in microRNA and microRNA biogenesis pathway genes and breast cancer risk among women of African ancestry.Hum Genet. 2016 Oct;135(10):1145-59. doi: 10.1007/s00439-016-1707-1. Epub 2016 Jul 5.
• [26] Perturbation of DROSHA and DICER expression by human papillomavirus 16 oncoproteins.Virology. 2017 Jul;507:192-198. doi: 10.1016/j.virol.2017.04.022. Epub 2017 Apr 24.
• [27] Association of polymorphisms in microRNA machinery genes (DROSHA, DICER1, RAN, and XPO5) with risk of idiopathic primary ovarian insufficiency in Korean women.Menopause. 2013 Oct;20(10):1067-73. doi: 10.1097/GME.0b013e3182883907.
• [28] The microRNA-processing enzymes: Drosha and Dicer can predict prognosis of nasopharyngeal carcinoma.J Cancer Res Clin Oncol. 2012 Jan;138(1):49-56. doi: 10.1007/s00432-011-1058-1. Epub 2011 Sep 28.
• [29] Neuronal activity regulates DROSHA via autophagy in spinal muscular atrophy.Sci Rep. 2018 May 21;8(1):7907. doi: 10.1038/s41598-018-26347-y.
• [30] DICER1, DROSHA and miRNAs in patients with non-small cell lung cancer: implications for outcomes and histologic classification.Carcinogenesis. 2013 May;34(5):1031-8. doi: 10.1093/carcin/bgt022. Epub 2013 Jan 24.
• [31] MicroRNA profiling of follicular lymphoma identifies microRNAs related to cell proliferation and tumor response.Haematologica. 2012 Apr;97(4):586-94. doi: 10.3324/haematol.2011.048132. Epub 2011 Nov 18.
• [32] Genetic variants in microRNA biogenesis pathway genes are associated with semen quality in a Han-Chinese population.Reprod Biomed Online. 2012 Apr;24(4):454-61. doi: 10.1016/j.rbmo.2012.01.006. Epub 2012 Jan 24.
• [33] RNASEN regulates cell proliferation and affects survival in esophageal cancer patients.Clin Cancer Res. 2006 Dec 15;12(24):7322-8. doi: 10.1158/1078-0432.CCR-06-0515. Epub 2006 Nov 22.
• [34] High-Throughput Data of Circular RNA Profiles in Human Temporal Cortex Tissue Reveals Novel Insights into Temporal Lobe Epilepsy.Cell Physiol Biochem. 2018;45(2):677-691. doi: 10.1159/000487161. Epub 2018 Jan 31.
• [35] 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.
• [36] 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.
• [37] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [38] 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.
• [39] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [40] 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.
• [41] 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.
• [42] 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.
• [43] Downregulation of miR-192 causes hepatic steatosis and lipid accumulation by inducing SREBF1: Novel mechanism for bisphenol A-triggered non-alcoholic fatty liver disease. Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Sep;1862(9):869-882. doi: 10.1016/j.bbalip.2017.05.001. Epub 2017 May 5.
• [44] 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.