Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRODIE5)

• DOT Name: rRNA 2'-O-methyltransferase fibrillarin (FBL)
• Synonyms: EC 2.1.1.-; 34 kDa nucleolar scleroderma antigen; Histone-glutamine methyltransferase; U6 snRNA 2'-O-methyltransferase fibrillarin
• Gene Name: FBL
• Related Disease:
  Autoimmune hepatitis
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiac failure
  Cholestasis
  Congestive heart failure
  Fatty liver disease
  Hepatic veno-occlusive disease
  Hepatitis
  Hepatitis A virus infection
  Hepatocellular carcinoma
  High blood pressure
  HIV infectious disease
  Liver cirrhosis
  Liver failure
  Lung adenocarcinoma
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Pancreatic cancer
  Primary sclerosing cholangitis
  Prostate cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Rheumatoid arthritis
  Systemic sclerosis
  Thrombocytopenia
  Urolithiasis
  Viral hepatitis
  Adrenoleukodystrophy
  Autoimmune disease
  Bacterial infection
  Cardiovascular disease
  Pulmonary tuberculosis
  Scleroderma
  Advanced cancer
  Anca-associated vasculitis
  Angioimmunoblastic T-cell Lymphoma
  Chronic kidney disease
  Chronic obstructive pulmonary disease
  Ductal breast carcinoma in situ
  Invasive ductal breast carcinoma
  Microscopic polyangiitis
  Non-alcoholic steatohepatitis
  Proliferative vitreoretinopathy
  Pulmonary emphysema
• UniProt ID: FBRL_HUMAN
• PDB ID: 2IPX; 7MQ8; 7MQ9; 7MQA; 7SE6; 7SE7; 7SE8; 7SE9; 7SEA; 7SEB; 7SEC; 7SED
• EC Number: 2.1.1.-
• Pfam ID: PF01269
• Sequence:
  MKPGFSPRGGGFGGRGGFGDRGGRGGRGGFGGGRGRGGGFRGRGRGGGGGGGGGGGGGRG
  GGGFHSGGNRGRGRGGKRGNQSGKNVMVEPHRHEGVFICRGKEDALVTKNLVPGESVYGE
  KRVSISEGDDKIEYRAWNPFRSKLAAAILGGVDQIHIKPGAKVLYLGAASGTTVSHVSDI
  VGPDGLVYAVEFSHRSGRDLINLAKKRTNIIPVIEDARHPHKYRMLIAMVDVIFADVAQP
  DQTRIVALNAHTFLRNGGHFVISIKANCIDSTASAEAVFASEVKKMQQENMKPQEQLTLE
  PYERDHAVVVGVYRPPPKVKN
• Function: S-adenosyl-L-methionine-dependent methyltransferase that has the ability to methylate both RNAs and proteins. Involved in pre-rRNA processing by catalyzing the site-specific 2'-hydroxyl methylation of ribose moieties in pre-ribosomal RNA. Site specificity is provided by a guide RNA that base pairs with the substrate. Methylation occurs at a characteristic distance from the sequence involved in base pairing with the guide RNA. Probably catalyzes 2'-O-methylation of U6 snRNAs in box C/D RNP complexes. U6 snRNA 2'-O-methylation is required for mRNA splicing fidelity. Also acts as a protein methyltransferase by mediating methylation of 'Gln-105' of histone H2A (H2AQ104me), a modification that impairs binding of the FACT complex and is specifically present at 35S ribosomal DNA locus. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)
• Reactome Pathway:
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune hepatitis	DISOX03Q	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Cholestasis	DISDJJWE	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[6]
Hepatic veno-occlusive disease	DISAIU45	Strong	Biomarker	[7]
Hepatitis	DISXXX35	Strong	Biomarker	[8]
Hepatitis A virus infection	DISUMFQV	Strong	Genetic Variation	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
High blood pressure	DISY2OHH	Strong	Biomarker	[11]
HIV infectious disease	DISO97HC	Strong	Biomarker	[12]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[13]
Liver failure	DISLGEL6	Strong	Genetic Variation	[14]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[17]
Obesity	DIS47Y1K	Strong	Biomarker	[18]
Pancreatic cancer	DISJC981	Strong	Biomarker	[2]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Biomarker	[19]
Prostate cancer	DISF190Y	Strong	Altered Expression	[20]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[20]
Pulmonary fibrosis	DISQKVLA	Strong	Genetic Variation	[21]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[11]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[22]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[23]
Urolithiasis	DISNFTKT	Strong	Biomarker	[24]
Viral hepatitis	DISVT5Q7	Strong	Biomarker	[9]
Adrenoleukodystrophy	DISTUD1F	moderate	Biomarker	[25]
Autoimmune disease	DISORMTM	moderate	Biomarker	[26]
Bacterial infection	DIS5QJ9S	moderate	Altered Expression	[27]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[28]
Pulmonary tuberculosis	DIS6FLUM	moderate	Biomarker	[29]
Scleroderma	DISVQ342	moderate	Biomarker	[22]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Anca-associated vasculitis	DISU3CNU	Limited	Biomarker	[30]
Angioimmunoblastic T-cell Lymphoma	DISZPFTL	Limited	Biomarker	[31]
Chronic kidney disease	DISW82R7	Limited	Biomarker	[32]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[33]
Ductal breast carcinoma in situ	DISLCJY7	Limited	Biomarker	[34]
Invasive ductal breast carcinoma	DIS43J58	Limited	Biomarker	[34]
Microscopic polyangiitis	DIS74KSO	Limited	Biomarker	[30]
Non-alcoholic steatohepatitis	DIST4788	Limited	Biomarker	[35]
Proliferative vitreoretinopathy	DISZTEK1	Limited	Genetic Variation	[36]
Pulmonary emphysema	DIS5M7HZ	Limited	Biomarker	[33]

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 rRNA 2'-O-methyltransferase fibrillarin (FBL).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[44]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[38]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[39]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[40]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[42]
Marinol	DM70IK5	Approved	Marinol decreases the expression of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[46]
biochanin A	DM0HPWY	Investigative	biochanin A increases the expression of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[47]

6 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin affects the localization of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[41]
Etoposide	DMNH3PG	Approved	Etoposide affects the localization of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[41]
Mitomycin	DMH0ZJE	Approved	Mitomycin affects the localization of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[41]
Dactinomycin	DM2YGNW	Approved	Dactinomycin affects the localization of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[41]
Lead acetate	DML0GZ2	Investigative	Lead acetate affects the localization of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[41]
5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole	DM3JB6S	Investigative	5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole affects the localization of rRNA 2'-O-methyltransferase fibrillarin (FBL).	[41]

References

• [1] Noninvasive indices for monitoring disease course in Chinese patients with autoimmune hepatitis.Clin Chim Acta. 2018 Nov;486:135-141. doi: 10.1016/j.cca.2018.07.030. Epub 2018 Jul 20.
• [2] Targeting the Ribosome Biogenesis Key Molecule Fibrillarin to Avoid Chemoresistance.Curr Med Chem. 2019;26(33):6020-6032. doi: 10.2174/0929867326666181203133332.
• [3] An integrative approach to identify YB-1-interacting proteins required for cisplatin resistance in MCF7 and MDA-MB-231 breast cancer cells. Cancer Sci. 2011 Jul;102(7):1410-7. doi: 10.1111/j.1349-7006.2011.01948.x. Epub 2011 May 5.
• [4] Fibrosis-4 index reflects right-sided filling pressure in patients with heart failure.Heart Vessels. 2020 Mar;35(3):376-383. doi: 10.1007/s00380-019-01505-y. Epub 2019 Sep 16.
• [5] The Clinical Significance of GP73 in Immunologically Mediated Chronic Liver Diseases: Experimental Data and Literature Review.Clin Rev Allergy Immunol. 2018 Apr;54(2):282-294. doi: 10.1007/s12016-017-8655-y.
• [6] Low Levels of Alcohol Consumption, Obesity, and Development of Fatty Liver With and Without Evidence of Advanced Fibrosis.Hepatology. 2020 Mar;71(3):861-873. doi: 10.1002/hep.30867. Epub 2019 Oct 10.
• [7] Estimation of the future remnant liver function is a better tool to predict post-hepatectomy liver failure than platelet-based liver scores.Eur J Surg Oncol. 2017 Dec;43(12):2277-2284. doi: 10.1016/j.ejso.2017.08.009. Epub 2017 Sep 4.
• [8] Utility and limitations of noninvasive fibrosis markers for predicting prognosis in biopsy-proven Japanese non-alcoholic fatty liver disease patients.J Gastroenterol Hepatol. 2019 Jan;34(1):207-214. doi: 10.1111/jgh.14448. Epub 2018 Sep 18.
• [9] Using AST-platelet ratio index and fibrosis 4 index for detecting chronic hepatitis C in a large-scale community screening.PLoS One. 2019 Oct 22;14(10):e0222196. doi: 10.1371/journal.pone.0222196. eCollection 2019.
• [10] Fibrosis-4, aspartate transaminase-to-platelet ratio index, and gamma-glutamyl transpeptidase-to-platelet ratio for risk assessment of hepatocellular carcinoma in chronic hepatitis B patients: comparison with liver biopsy.Eur J Gastroenterol Hepatol. 2020 Mar;32(3):433-439. doi: 10.1097/MEG.0000000000001520.
• [11] Fibrosis-4 index at diagnosis can predict all-cause mortality in patients with rheumatoid arthritis: A retrospective monocentric study.Mod Rheumatol. 2020 Jan;30(1):70-77. doi: 10.1080/14397595.2018.1558760. Epub 2019 Jan 15.
• [12] Associations of Liver Disease with Alcohol Use among People Living with HIV and the Role of Hepatitis C: The New Orleans Alcohol Use in HIV Study.Alcohol Alcohol. 2020 Feb 7;55(1):28-36. doi: 10.1093/alcalc/agz089.
• [13] Hepatitis C Virus (HCV) Treatment With Directly Acting Agents Reduces the Risk of Incident Diabetes: Results From Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES).Clin Infect Dis. 2020 Mar 3;70(6):1153-1160. doi: 10.1093/cid/ciz304.
• [14] The preoperative fibrosis score 4 predicts posthepatectomy liver failure in patients with hepatocellular carcinoma.Ann Hepatol. 2019 Sep-Oct;18(5):701-707. doi: 10.1016/j.aohep.2019.04.017. Epub 2019 May 26.
• [15] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [16] Quantitative time-resolved chemoproteomics reveals that stable O-GlcNAc regulates box C/D snoRNP biogenesis.Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):E6749-E6758. doi: 10.1073/pnas.1702688114. Epub 2017 Jul 31.
• [17] Trend over time in hepatic fibrosis score in a cohort of type 2 diabetes patients.Diabetes Res Clin Pract. 2018 Jan;135:65-72. doi: 10.1016/j.diabres.2017.10.023. Epub 2017 Oct 31.
• [18] Impact of Obesity and Alanine Aminotransferase Levels on the Diagnostic Accuracy for Advanced Liver Fibrosis of Noninvasive Tools in Patients With Nonalcoholic Fatty Liver Disease.Am J Gastroenterol. 2019 Jun;114(6):916-928. doi: 10.14309/ajg.0000000000000153.
• [19] Primary sclerosing cholangitis: diagnostic performance of MRI compared to blood tests and clinical scoring systems for the evaluation of histopathological severity of disease.Abdom Radiol (NY). 2020 Feb;45(2):354-364. doi: 10.1007/s00261-019-02366-9.
• [20] Comparative transcriptional study of the effects of high intracellular zinc on prostate carcinoma cells.Oncol Rep. 2010 Jun;23(6):1501-16. doi: 10.3892/or_00000789.
• [21] Ethnicity and race and systemic sclerosis: how it affects susceptibility, severity, antibody genetics, and clinical manifestations.Curr Rheumatol Rep. 2003 Apr;5(2):160-7. doi: 10.1007/s11926-003-0045-1.
• [22] U3 snoRNP associates with fibrillarin a component of the scleroderma clumpy nucleolar domain.Arch Dermatol Res. 2002 Oct;294(7):310-7. doi: 10.1007/s00403-002-0338-7. Epub 2002 Sep 5.
• [23] Changes in biomarkers of liver disease during successful combination antiretroviral therapy in HIV-HCV-coinfected individuals.Antivir Ther. 2014;19(2):149-59. doi: 10.3851/IMP2686. Epub 2013 Sep 13.
• [24] The association between a non-invasive hepatic fibrosis score and urolithiasis among non-alcoholic fatty liver disease (NAFLD) patients in China: a cross-sectional study.BMJ Open. 2019 Aug 30;9(8):e027702. doi: 10.1136/bmjopen-2018-027702.
• [25] Non-invasive diagnosis and biomarkers in alcohol-related liver disease.J Hepatol. 2019 Feb;70(2):273-283. doi: 10.1016/j.jhep.2018.11.025.
• [26] Gold- and silver-induced murine autoimmunity--requirement for cytokines and CD28 in murine heavy metal-induced autoimmunity.Clin Exp Immunol. 2009 Mar;155(3):567-76. doi: 10.1111/j.1365-2249.2008.03831.x. Epub 2008 Dec 5.
• [27] Nucleolar fibrillarin is an evolutionarily conserved regulator of bacterial pathogen resistance.Nat Commun. 2018 Sep 6;9(1):3607. doi: 10.1038/s41467-018-06051-1.
• [28] MiR-92a contributes to the cardiovascular disease development in diabetes mellitus through NF-B and downstream inflammatory pathways.Eur Rev Med Pharmacol Sci. 2019 Apr;23(7):3070-3079. doi: 10.26355/eurrev_201904_17589.
• [29] Serum amyloid A, protein Z, and C4b-binding protein chain as new potential biomarkers for pulmonary tuberculosis.PLoS One. 2017 Mar 9;12(3):e0173304. doi: 10.1371/journal.pone.0173304. eCollection 2017.
• [30] Fibrosis-4 index at diagnosis is associated with all-cause mortality in patients with microscopic polyangiitis and granulomatosis with polyangiitis.BMC Gastroenterol. 2019 Jun 13;19(1):90. doi: 10.1186/s12876-019-1007-z.
• [31] Diagnostic performance of a point shear wave elastography (pSWE) for hepatic fibrosis in patients with autoimmune liver disease.PLoS One. 2019 Mar 11;14(3):e0212771. doi: 10.1371/journal.pone.0212771. eCollection 2019.
• [32] Liver stiffness assessed by transient elastography as a potential indicator of chronic kidney disease in patients with nonalcoholic fatty liver disease.J Clin Lab Anal. 2019 Feb;33(2):e22657. doi: 10.1002/jcla.22657. Epub 2018 Sep 21.
• [33] End-product of fibrinogen is elevated in emphysematous chronic obstructive pulmonary disease and is predictive of mortality in the ECLIPSE cohort.Respir Med. 2019 Nov-Dec;160:105814. doi: 10.1016/j.rmed.2019.105814. Epub 2019 Nov 6.
• [34] Differential expression of follistatin and FLRG in human breast proliferative disorders.BMC Cancer. 2009 Sep 9;9:320. doi: 10.1186/1471-2407-9-320.
• [35] Ability of Cytokeratin-18 Fragments and FIB-4 Index to Diagnose Overall and Mild Fibrosis Nonalcoholic Steatohepatitis in Japanese Nonalcoholic Fatty Liver Disease Patients.Dig Dis. 2017;35(6):521-530. doi: 10.1159/000480142. Epub 2017 Oct 17.
• [36] Relationship between virological response and FIB-4 index in chronic hepatitis B patients with entecavir therapy.World J Gastroenterol. 2015 Nov 21;21(43):12421-9. doi: 10.3748/wjg.v21.i43.12421.
• [37] 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.
• [38] 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.
• [39] 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.
• [40] 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.
• [41] Specific inhibition of rRNA transcription and dynamic relocation of fibrillarin induced by mercury. Exp Cell Res. 2000 Aug 25;259(1):225-38. doi: 10.1006/excr.2000.4923.
• [42] 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.
• [43] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [44] 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.
• [45] 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.
• [46] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [47] Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate. 2002 Aug 1;52(3):201-12.