Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA580RX)

• DOT Name: H/ACA ribonucleoprotein complex subunit 1 (GAR1)
• Synonyms: Nucleolar protein family A member 1; snoRNP protein GAR1
• Gene Name: GAR1
• Related Disease:
  Dyskeratosis congenita
  Acquired aplastic anemia
  Dyskeratosis congenita, X-linked
  Hematologic disease
  Lung adenocarcinoma
  Small lymphocytic lymphoma
• UniProt ID: GAR1_HUMAN
• PDB ID: 7BGB; 7TRC; 7V9A
• Pfam ID: PF04410
• Sequence:
  MSFRGGGRGGFNRGGGGGGFNRGGSSNHFRGGGGGGGGGNFRGGGRGGFGRGGGRGGFNK
  GQDQGPPERVVLLGEFLHPCEDDIVCKCTTDENKVPYFNAPVYLENKEQIGKVDEIFGQL
  RDFYFSVKLSENMKASSFKKLQKFYIDPYKLLPLQRFLPRPPGEKGPPRGGGRGGRGGGR
  GGGGRGGGRGGGFRGGRGGGGGGFRGGRGGGFRGRGH
• Function: Required for ribosome biogenesis and telomere maintenance. Part of the H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA. This involves the isomerization of uridine such that the ribose is subsequently attached to C5, instead of the normal N1. Each rRNA can contain up to 100 pseudouridine ('psi') residues, which may serve to stabilize the conformation of rRNAs. May also be required for correct processing or intranuclear trafficking of TERC, the RNA component of the telomerase reverse transcriptase (TERT) holoenzyme.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)
• Reactome Pathway:
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)
  Telomere Extension By Telomerase (R-HSA-171319)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dyskeratosis congenita	DISSXV0K	Definitive	Biomarker	[1]
Acquired aplastic anemia	DISCMKMX	Strong	Genetic Variation	[2]
Dyskeratosis congenita, X-linked	DISJ3Y69	Strong	Biomarker	[1]
Hematologic disease	DIS9XD9A	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[3]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[4]

2 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 H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[14]

10 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 H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of H/ACA ribonucleoprotein complex subunit 1 (GAR1).	[16]

References

• [1] Zebrafish models for dyskeratosis congenita reveal critical roles of p53 activation contributing to hematopoietic defects through RNA processing.PLoS One. 2012;7(1):e30188. doi: 10.1371/journal.pone.0030188. Epub 2012 Jan 27.
• [2] NOLA1 gene mutations in acquired aplastic anemia.Pediatr Blood Cancer. 2009 Mar;52(3):376-8. doi: 10.1002/pbc.21813.
• [3] 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.
• [4] Dysregulation of H/ACA ribonucleoprotein components in chronic lymphocytic leukemia.PLoS One. 2017 Jun 30;12(6):e0179883. doi: 10.1371/journal.pone.0179883. eCollection 2017.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [12] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [13] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [14] 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.
• [15] 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.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.