Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUA4OLZ)

• DOT Name: U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3)
• Synonyms: Pre-mRNA-splicing factor 3; hPrp3; U4/U6 snRNP 90 kDa protein
• Gene Name: PRPF3
• Related Disease:
  Retinitis pigmentosa 18
  Breast cancer
  Breast carcinoma
  Neoplasm
  Retinal degeneration
  Osteoarthritis
  Retinitis pigmentosa
  Retinitis pigmentosa 13
• UniProt ID: PRPF3_HUMAN
• PDB ID: 1X4Q; 3JCR; 5O9Z; 6AH0; 6AHD; 6QW6; 6QX9; 7N2N; 7N2R; 7N2S
• Pfam ID: PF08572 ; PF06544 ; PF01480
• Sequence:
  MALSKRELDELKPWIEKTVKRVLGFSEPTVVTAALNCVGKGMDKKKAADHLKPFLDDSTL
  RFVDKLFEAVEEGRSSRHSKSSSDRSRKRELKEVFGDDSEISKESSGVKKRRIPRFEEVE
  EEPEVIPGPPSESPGMLTKLQIKQMMEAATRQIEERKKQLSFISPPTPQPKTPSSSQPER
  LPIGNTIQPSQAATFMNDAIEKARKAAELQARIQAQLALKPGLIGNANMVGLANLHAMGI
  APPKVELKDQTKPTPLILDEQGRTVDATGKEIELTHRMPTLKANIRAVKREQFKQQLKEK
  PSEDMESNTFFDPRVSIAPSQRQRRTFKFHDKGKFEKIAQRLRTKAQLEKLQAEISQAAR
  KTGIHTSTRLALIAPKKELKEGDIPEIEWWDSYIIPNGFDLTEENPKREDYFGITNLVEH
  PAQLNPPVDNDTPVTLGVYLTKKEQKKLRRQTRREAQKELQEKVRLGLMPPPEPKVRISN
  LMRVLGTEAVQDPTKVEAHVRAQMAKRQKAHEEANAARKLTAEQRKVKKIKKLKEDISQG
  VHISVYRVRNLSNPAKKFKIEANAGQLYLTGVVVLHKDVNVVVVEGGPKAQKKFKRLMLH
  RIKWDEQTSNTKGDDDEESDEEAVKKTNKCVLVWEGTAKDRSFGEMKFKQCPTENMAREH
  FKKHGAEHYWDLALSESVLESTD
• Function: Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex).
• Tissue Specificity: Highly expressed in retina, liver, kidney and blood. Detected at lower levels in heart and brain.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Retinitis pigmentosa 18	DIS9LWX6	Definitive	Autosomal dominant	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Retinal degeneration	DISM1JHQ	Strong	Genetic Variation	[4]
Osteoarthritis	DIS05URM	moderate	Biomarker	[5]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[6]
Retinitis pigmentosa 13	DISXKU6Y	Limited	Biomarker	[7]

9 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 U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of U4/U6 small nuclear ribonucleoprotein Prp3 (PRPF3).	[16]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] 22 genes from chromosome 17q21: cloning, sequencing, and characterization of mutations in breast cancer families and tumors.Genomics. 1995 Jan 1;25(1):256-63. doi: 10.1016/0888-7543(95)80133-7.
• [3] Precursor RNA processing 3 is required for male fertility, and germline stem cell self-renewal and differentiation via regulating spliceosome function in Drosophila testes.Sci Rep. 2019 Jul 10;9(1):9988. doi: 10.1038/s41598-019-46419-x.
• [4] Mutations in splicing factor PRPF3, causing retinal degeneration, form detrimental aggregates in photoreceptor cells.Hum Mol Genet. 2007 Jul 15;16(14):1699-707. doi: 10.1093/hmg/ddm118. Epub 2007 May 20.
• [5] Multiple Platelet-Rich Plasma Injections Versus Single Platelet-Rich Plasma Injection in Early Osteoarthritis of the Knee: An Experimental Study in a Guinea Pig Model of Early Knee Osteoarthritis.Am J Sports Med. 2019 Aug;47(10):2300-2307. doi: 10.1177/0363546519856605. Epub 2019 Jul 3.
• [6] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [7] Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex: possible role in autosomal dominant retinitis pigmentosa.Mol Vis. 2008 Jan 25;14:125-35.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] 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.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [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] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [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] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.