Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3X7QG2)

• DOT Name: 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2)
• Synonyms: Elongation factor Tu GTP-binding domain-containing protein 2; SNU114 homolog; hSNU114; U5 snRNP-specific protein, 116 kDa; U5-116 kDa
• Gene Name: EFTUD2
• Related Disease:
  Dysplasia
  Mandibulofacial dysostosis-microcephaly syndrome
  Colitis
  Colorectal neoplasm
  Congenital radioulnar synostosis
  Craniofacial microsomia
  Intellectual disability
  Isolated congenital microcephaly
  Retinitis pigmentosa
  Treacher-Collins syndrome
  Nervous system disease
  Osteochondrodysplasia
  Skeletal dysplasia
• UniProt ID: U5S1_HUMAN
• PDB ID: 3JCR; 5MQF; 5O9Z; 5XJC; 5YZG; 5Z56; 5Z57; 5Z58; 6AH0; 6AHD; 6FF4; 6FF7; 6ICZ; 6ID0; 6ID1; 6QDV; 6QW6; 6QX9; 6ZYM; 7AAV; 7ABF; 7ABG; 7ABI; 7DVQ; 7QTT; 7W59; 7W5A; 7W5B; 8C6J; 8CH6
• Pfam ID: PF00679 ; PF14492 ; PF03764 ; PF16004 ; PF00009 ; PF03144
• Sequence:
  MDTDLYDEFGNYIGPELDSDEDDDELGRETKDLDEMDDDDDDDDVGDHDDDHPGMEVVLH
  EDKKYYPTAEEVYGPEVETIVQEEDTQPLTEPIIKPVKTKKFTLMEQTLPVTVYEMDFLA
  DLMDNSELIRNVTLCGHLHHGKTCFVDCLIEQTHPEIRKRYDQDLCYTDILFTEQERGVG
  IKSTPVTVVLPDTKGKSYLFNIMDTPGHVNFSDEVTAGLRISDGVVLFIDAAEGVMLNTE
  RLIKHAVQERLAVTVCINKIDRLILELKLPPTDAYYKLRHIVDEVNGLISMYSTDENLIL
  SPLLGNVCFSSSQYSICFTLGSFAKIYADTFGDINYQEFAKRLWGDIYFNPKTRKFTKKA
  PTSSSQRSFVEFILEPLYKILAQVVGDVDTSLPRTLDELGIHLTKEELKLNIRPLLRLVC
  KKFFGEFTGFVDMCVQHIPSPKVGAKPKIEHTYTGGVDSDLGEAMSDCDPDGPLMCHTTK
  MYSTDDGVQFHAFGRVLSGTIHAGQPVKVLGENYTLEDEEDSQICTVGRLWISVARYHIE
  VNRVPAGNWVLIEGVDQPIVKTATITEPRGNEEAQIFRPLKFNTTSVIKIAVEPVNPSEL
  PKMLDGLRKVNKSYPSLTTKVEESGEHVILGTGELYLDCVMHDLRKMYSEIDIKVADPVV
  TFCETVVETSSLKCFAETPNKKNKITMIAEPLEKGLAEDIENEVVQITWNRKKLGEFFQT
  KYDWDLLAARSIWAFGPDATGPNILVDDTLPSEVDKALLGSVKDSIVQGFQWGTREGPLC
  DELIRNVKFKILDAVVAQEPLHRGGGQIIPTARRVVYSAFLMATPRLMEPYYFVEVQAPA
  DCVSAVYTVLARRRGHVTQDAPIPGSPLYTIKAFIPAIDSFGFETDLRTHTQGQAFSLSV
  FHHWQIVPGDPLDKSIVIRPLEPQPAPHLAREFMIKTRRRKGLSEDVSISKFFDDPMLLE
  LAKQDVVLNYPM
• Function: Required for pre-mRNA splicing as component of the spliceosome, including pre-catalytic, catalytic and post-catalytic spliceosomal complexes. Component of the U5 snRNP and the U4/U6-U5 tri-snRNP complex, a building block of the spliceosome. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable).
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway:
  mRNA Splicing - Minor Pathway (R-HSA-72165)
  mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dysplasia	DISHPNVX	Definitive	Genetic Variation	[1]
Mandibulofacial dysostosis-microcephaly syndrome	DISSZWPO	Definitive	Autosomal dominant	[2]
Colitis	DISAF7DD	Strong	Biomarker	[3]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[3]
Congenital radioulnar synostosis	DISF96QX	Strong	Biomarker	[1]
Craniofacial microsomia	DISYHJ2P	Strong	Genetic Variation	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[6]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[7]
Treacher-Collins syndrome	DIS2GXZ1	Strong	Genetic Variation	[8]
Nervous system disease	DISJ7GGT	Disputed	Biomarker	[9]
Osteochondrodysplasia	DIS9SPWW	Limited	Biomarker	[6]
Skeletal dysplasia	DIS5Z8U6	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2) affects the response to substance of Acetaminophen.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2).	[11]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2).	[18]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2).	[19]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the phosphorylation of 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2).	[16]

References

• [1] Radioulnar Synostosis and Brain Abnormalities in a Patient With 17q21.31 Microdeletion Involving EFTUD2.Cleft Palate Craniofac J. 2015 Mar;52(2):237-9. doi: 10.1597/13-221. Epub 2014 May 7.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Spliceosome protein Eftud2 promotes colitis-associated tumorigenesis by modulating inflammatory response of macrophage.Mucosal Immunol. 2019 Sep;12(5):1164-1173. doi: 10.1038/s41385-019-0184-y. Epub 2019 Jul 5.
• [4] EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia.J Med Genet. 2012 Dec;49(12):737-46. doi: 10.1136/jmedgenet-2012-101173.
• [5] Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. Genet Med. 2016 Jan;18(1):49-56. doi: 10.1038/gim.2015.29. Epub 2015 Mar 19.
• [6] EFTUD2 gene deficiency disrupts osteoblast maturation and inhibits chondrocyte differentiation via activation of the p53 signaling pathway.Hum Genomics. 2019 Dec 5;13(1):63. doi: 10.1186/s40246-019-0238-y.
• [7] Structure of a multipartite protein-protein interaction domain in splicing factor prp8 and its link to retinitis pigmentosa.Mol Cell. 2007 Feb 23;25(4):615-24. doi: 10.1016/j.molcel.2007.01.023.
• [8] A review of craniofacial disorders caused by spliceosomal defects.Clin Genet. 2015 Nov;88(5):405-15. doi: 10.1111/cge.12596. Epub 2015 May 1.
• [9] Spliceosomal protein eftud2 mutation leads to p53-dependent apoptosis in zebrafish neural progenitors.Nucleic Acids Res. 2017 Apr 7;45(6):3422-3436. doi: 10.1093/nar/gkw1043.
• [10] 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.
• [11] 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.
• [12] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [13] Phosphoproteomics reveals resveratrol-dependent inhibition of Akt/mTORC1/S6K1 signaling. J Proteome Res. 2014 Dec 5;13(12):5734-42. doi: 10.1021/pr500714a. Epub 2014 Oct 29.
• [14] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [15] 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.
• [16] 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.
• [17] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [20] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.
• [21] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.