Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGB9OR9)

• DOT Name: Splicing factor 3B subunit 4 (SF3B4)
• Synonyms: Pre-mRNA-splicing factor SF3b 49 kDa subunit; Spliceosome-associated protein 49; SAP 49
• Gene Name: SF3B4
• Related Disease:
  Nager acrofacial dysostosis
  SF3B4-related acrofacial dysostosis
  Acrofacial dysostosis
  Dysplasia
  Giardiasis
  Hepatocellular carcinoma
  Pancreatic cancer
  Acrofacial dysostosis Rodriguez type
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Neoplasm
• UniProt ID: SF3B4_HUMAN
• PDB ID: 1X5T; 5GVQ; 5Z56; 5Z57; 5Z58; 6AH0; 6AHD; 6QX9; 6Y53; 6Y5Q; 7ABG; 7ABH; 7ABI; 7DVQ; 7EVO; 7ONB; 7QTT; 7VPX; 8CH6; 8HK1
• Pfam ID: PF00076
• Sequence:
  MAAGPISERNQDATVYVGGLDEKVSEPLLWELFLQAGPVVNTHMPKDRVTGQHQGYGFVE
  FLSEEDADYAIKIMNMIKLYGKPIRVNKASAHNKNLDVGANIFIGNLDPEIDEKLLYDTF
  SAFGVILQTPKIMRDPDTGNSKGYAFINFASFDASDAAIEAMNGQYLCNRPITVSYAFKK
  DSKGERHGSAAERLLAAQNPLSQADRPHQLFADAPPPPSAPNPVVSSLGSGLPPPGMPPP
  GSFPPPVPPPGALPPGIPPAMPPPPMPPGAAGHGPPSAGTPGAGHPGHGHSHPHPFPPGG
  MPHPGMSQMQLAHHGPHGLGHPHAGPPGSGGQPPPRPPPGMPHPGPPPMGMPPRGPPFGS
  PMGHPGPMPPHGMRGPPPLMPPHGYTGPPRPPPYGYQRGPLPPPRPTPRPPVPPRGPLRG
  PLPQ
• Function: Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs. The 17S U2 SnRNP complex (1) directly participates in early spliceosome assembly and (2) mediates recognition of the intron branch site during pre-mRNA splicing by promoting the selection of the pre-mRNA branch-site adenosine, the nucleophile for the first step of splicing. Within the 17S U2 SnRNP complex, SF3B4 is part of the SF3B subcomplex, which is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence in pre-mRNA. Sequence independent binding of SF3A and SF3B subcomplexes upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. Also acts as a component of the minor spliceosome, which is involved in the splicing of U12-type introns in pre-mRNAs.
• 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

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nager acrofacial dysostosis	DIS9WQOT	Definitive	Autosomal dominant	[1]
SF3B4-related acrofacial dysostosis	DIS9A5IP	Definitive	Autosomal dominant	[2]
Acrofacial dysostosis	DISNBM5T	Strong	Genetic Variation	[3]
Dysplasia	DISHPNVX	Strong	Genetic Variation	[3]
Giardiasis	DISWUNWK	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Pancreatic cancer	DISJC981	moderate	Biomarker	[6]
Acrofacial dysostosis Rodriguez type	DISGV1RL	Supportive	Autosomal dominant	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[5]
Liver cancer	DISDE4BI	Limited	Biomarker	[5]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]

12 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 Splicing factor 3B subunit 4 (SF3B4).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Splicing factor 3B subunit 4 (SF3B4).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Splicing factor 3B subunit 4 (SF3B4).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Splicing factor 3B subunit 4 (SF3B4).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Splicing factor 3B subunit 4 (SF3B4).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Splicing factor 3B subunit 4 (SF3B4).	[14]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Splicing factor 3B subunit 4 (SF3B4).	[15]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Splicing factor 3B subunit 4 (SF3B4).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Splicing factor 3B subunit 4 (SF3B4).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Splicing factor 3B subunit 4 (SF3B4).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Splicing factor 3B subunit 4 (SF3B4).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Splicing factor 3B subunit 4 (SF3B4).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Splicing factor 3B subunit 4 (SF3B4).	[11]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis.PLoS Genet. 2016 Sep 13;12(9):e1006307. doi: 10.1371/journal.pgen.1006307. eCollection 2016 Sep.
• [4] Patterns of conservation of spliceosomal intron structures and spliceosome divergence in representatives of the diplomonad and parabasalid lineages.BMC Evol Biol. 2019 Aug 2;19(1):162. doi: 10.1186/s12862-019-1488-y.
• [5] SF3B4 as an early-stage diagnostic marker and driver of hepatocellular carcinoma.BMB Rep. 2018 Feb;51(2):57-58. doi: 10.5483/bmbrep.2018.51.2.021.
• [6] SF3B4 is decreased in pancreatic cancer and inhibits the growth and migration of cancer cells.Tumour Biol. 2017 Mar;39(3):1010428317695913. doi: 10.1177/1010428317695913.
• [7] Rodriguez acrofacial dysostosis is caused by apparently de novo heterozygous mutations in the SF3B4 gene. Am J Med Genet A. 2016 Dec;170(12):3133-3137. doi: 10.1002/ajmg.a.37946. Epub 2016 Sep 19.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [16] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [17] Benzo[a]pyrene treatment leads to changes in nuclear protein expression and alternative splicing. Mutat Res. 2010 Apr 1;686(1-2):47-56. doi: 10.1016/j.mrfmmm.2010.01.015. Epub 2010 Jan 25.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.