Details of Drug Off-Target (DOT)

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

• DOT Name: tRNA pseudouridine synthase Pus10 (PUS10)
• Synonyms: Hup10; EC 5.4.99.25; Coiled-coil domain-containing protein 139; tRNA pseudouridine 55 synthase; Psi55 synthase; tRNA pseudouridylate synthase; tRNA-uridine isomerase
• Gene Name: PUS10
• Related Disease:
  Atopic dermatitis
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Coeliac disease
  Crohn disease
  Multiple sclerosis
  Primary sclerosing cholangitis
  STAT3-related early-onset multisystem autoimmune disease
  Asthma
  Immune system disorder
  Ankylosing spondylitis
  Inflammatory bowel disease
  Psoriasis
  Sclerosing cholangitis
  Ulcerative colitis
• UniProt ID: PUS10_HUMAN
• PDB ID: 2V9K
• EC Number: 5.4.99.25
• Pfam ID: PF21238 ; PF21237
• Sequence:
  MFPLTEENKHVAQLLLNTGTCPRCIFRFCGVDFHAPYKLPYKELLNELQKFLETEKDELI
  LEVMNPPPKKIRLQELEDSIDNLSQNGEGRISVSHVGSTASKNSNLNVCNVCLGILQEFC
  EKDFIKKVCQKVEASGFEFTSLVFSVSFPPQLSVREHAAWLLVKQEMGKQSLSLGRDDIV
  QLKEAYKWITHPLFSEELGVPIDGKSLFEVSVVFAHPETVEDCHFLAAICPDCFKPAKNK
  QSVFTRMAVMKALNKIKEEDFLKQFPCPPNSPKAVCAVLEIECAHGAVFVAGRYNKYSRN
  LPQTPWIIDGERKLESSVEELISDHLLAVFKAESFNFSSSGREDVDVRTLGNGRPFAIEL
  VNPHRVHFTSQEIKELQQKINNSSNKIQVRDLQLVTREAIGHMKEGEEEKTKTYSALIWT
  NKAIQKKDIEFLNDIKDLKIDQKTPLRVLHRRPLAVRARVIHFMETQYVDEHHFRLHLKT
  QAGTYIKEFVHGDFGRTKPNIGSLMNVTADILELDVESVDVDWPPALDD
• Function: Protein with different functions depending on its subcellular location: involved in miRNA processing in the nucleus and acts as a tRNA pseudouridylate synthase in the cytoplasm. In the cytoplasm, acts as a pseudouridylate synthase by catalyzing synthesis of pseudouridine(54) and pseudouridine(55) from uracil-54 and uracil-55, respectively, in the psi GC loop of a subset of tRNAs. tRNA pseudouridylate synthase activity is enhanced by the presence of 1-methyladenosine at position 53-61 of tRNAs. Does not show tRNA pseudouridylate synthase activity in the nucleus. In the nucleus, promotes primary microRNAs (pri-miRNAs) processing independently of its RNA pseudouridylate synthase activity. Binds pri-miRNAs. Modulator of TRAIL/TNFSF10-induced cell death via activation of procaspase-8 and BID cleavage. Required for the progression of the apoptotic signal through intrinsic mitochondrial cell death.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[2]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[2]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[3]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[4]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[5]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Genetic Variation	[6]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[2]
Asthma	DISW9QNS	moderate	Genetic Variation	[7]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[8]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[9]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[4]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[9]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[9]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[4]

10 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 tRNA pseudouridine synthase Pus10 (PUS10).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of tRNA pseudouridine synthase Pus10 (PUS10).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of tRNA pseudouridine synthase Pus10 (PUS10).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA pseudouridine synthase Pus10 (PUS10).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of tRNA pseudouridine synthase Pus10 (PUS10).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of tRNA pseudouridine synthase Pus10 (PUS10).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of tRNA pseudouridine synthase Pus10 (PUS10).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of tRNA pseudouridine synthase Pus10 (PUS10).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of tRNA pseudouridine synthase Pus10 (PUS10).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of tRNA pseudouridine synthase Pus10 (PUS10).	[19]

References

• [1] Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.Nat Genet. 2015 Dec;47(12):1449-1456. doi: 10.1038/ng.3424. Epub 2015 Oct 19.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.Nat Genet. 2012 Dec;44(12):1336-40. doi: 10.1038/ng.2462. Epub 2012 Nov 11.
• [4] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [5] Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
• [6] Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.Nat Genet. 2013 Jun;45(6):670-5. doi: 10.1038/ng.2616. Epub 2013 Apr 21.
• [7] Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.Eur J Hum Genet. 2011 Apr;19(4):458-64. doi: 10.1038/ejhg.2010.191. Epub 2010 Dec 8.
• [8] Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.PLoS Genet. 2011 Feb;7(2):e1002004. doi: 10.1371/journal.pgen.1002004. Epub 2011 Feb 24.
• [9] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] 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.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [18] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.