Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAC9LZT)

• DOT Name: Splicing factor 3B subunit 3 (SF3B3)
• Synonyms: Pre-mRNA-splicing factor SF3b 130 kDa subunit; SF3b130; STAF130; Spliceosome-associated protein 130; SAP 130
• Gene Name: SF3B3
• Related Disease:
  Advanced cancer
  Alcoholic liver diseases
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Crohn disease
  Kidney cancer
  Neoplasm
  Non-small-cell lung cancer
  Renal carcinoma
  Hepatocellular carcinoma
  High blood pressure
• UniProt ID: SF3B3_HUMAN
• PDB ID: 5IFE ; 5O9Z ; 5Z56 ; 5Z57 ; 5Z58 ; 5ZYA ; 6AH0 ; 6AHD ; 6EN4 ; 6FF4 ; 6FF7 ; 6QX9 ; 6Y50 ; 6Y5Q ; 7ABG ; 7ABH ; 7ABI ; 7B0I ; 7B91 ; 7B92 ; 7B9C ; 7DVQ ; 7EVN ; 7EVO ; 7KTS ; 7OMF ; 7ONB ; 7OPI ; 7Q3L ; 7Q4O ; 7Q4P ; 7QTT ; 7VPX ; 8CH6 ; 8H7G ; 8HK1
• Pfam ID: PF03178 ; PF10433
• Sequence:
  MFLYNLTLQRATGISFAIHGNFSGTKQQEIVVSRGKILELLRPDPNTGKVHTLLTVEVFG
  VIRSLMAFRLTGGTKDYIVVGSDSGRIVILEYQPSKNMFEKIHQETFGKSGCRRIVPGQF
  LAVDPKGRAVMISAIEKQKLVYILNRDAAARLTISSPLEAHKANTLVYHVVGVDVGFENP
  MFACLEMDYEEADNDPTGEAAANTQQTLTFYELDLGLNHVVRKYSEPLEEHGNFLITVPG
  GSDGPSGVLICSENYITYKNFGDQPDIRCPIPRRRNDLDDPERGMIFVCSATHKTKSMFF
  FLAQTEQGDIFKITLETDEDMVTEIRLKYFDTVPVAAAMCVLKTGFLFVASEFGNHYLYQ
  IAHLGDDDEEPEFSSAMPLEEGDTFFFQPRPLKNLVLVDELDSLSPILFCQIADLANEDT
  PQLYVACGRGPRSSLRVLRHGLEVSEMAVSELPGNPNAVWTVRRHIEDEFDAYIIVSFVN
  ATLVLSIGETVEEVTDSGFLGTTPTLSCSLLGDDALVQVYPDGIRHIRADKRVNEWKTPG
  KKTIVKCAVNQRQVVIALTGGELVYFEMDPSGQLNEYTERKEMSADVVCMSLANVPPGEQ
  RSRFLAVGLVDNTVRIISLDPSDCLQPLSMQALPAQPESLCIVEMGGTEKQDELGERGSI
  GFLYLNIGLQNGVLLRTVLDPVTGDLSDTRTRYLGSRPVKLFRVRMQGQEAVLAMSSRSW
  LSYSYQSRFHLTPLSYETLEFASGFASEQCPEGIVAISTNTLRILALEKLGAVFNQVAFP
  LQYTPRKFVIHPESNNLIIIETDHNAYTEATKAQRKQQMAEEMVEAAGEDERELAAEMAA
  AFLNENLPESIFGAPKAGNGQWASVIRVMNPIQGNTLDLVQLEQNEAAFSVAVCRFSNTG
  EDWYVLVGVAKDLILNPRSVAGGFVYTYKLVNNGEKLEFLHKTPVEEVPAAIAPFQGRVL
  IGVGKLLRVYDLGKKKLLRKCENKHIANYISGIQTIGHRVIVSDVQESFIWVRYKRNENQ
  LIIFADDTYPRWVTTASLLDYDTVAGADKFGNICVVRLPPNTNDEVDEDPTGNKALWDRG
  LLNGASQKAEVIMNYHVGETVLSLQKTTLIPGGSESLVYTTLSGGIGILVPFTSHEDHDF
  FQHVEMHLRSEHPPLCGRDHLSFRSYYFPVKNVIDGDLCEQFNSMEPNKQKNVSEELDRT
  PPEVSKKLEDIRTRYAF
• 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, SF3B3 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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alcoholic liver diseases	DISXEPHQ	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[1]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[4]
Kidney cancer	DISBIPKM	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	moderate	Genetic Variation	[6]
High blood pressure	DISY2OHH	moderate	Biomarker	[7]

3 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 Splicing factor 3B subunit 3 (SF3B3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Splicing factor 3B subunit 3 (SF3B3).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Splicing factor 3B subunit 3 (SF3B3).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Splicing factor 3B subunit 3 (SF3B3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Splicing factor 3B subunit 3 (SF3B3).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Splicing factor 3B subunit 3 (SF3B3).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Splicing factor 3B subunit 3 (SF3B3).	[13]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Splicing factor 3B subunit 3 (SF3B3).	[14]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of Splicing factor 3B subunit 3 (SF3B3).	[18]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin affects the binding of Splicing factor 3B subunit 3 (SF3B3).	[12]
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Splicing factor 3B subunit 3 (SF3B3).	[15]

References

• [1] Alternative Splicing of EZH2 pre-mRNA by SF3B3 Contributes to the Tumorigenic Potential of Renal Cancer.Clin Cancer Res. 2017 Jul 1;23(13):3428-3441. doi: 10.1158/1078-0432.CCR-16-2020. Epub 2016 Nov 22.
• [2] Spliceosome-Associated Protein 130 Exacerbates Alcohol-Induced Liver Injury by Inducing NLRP3 Inflammasome-Mediated IL-1 in Mice.Am J Pathol. 2018 Apr;188(4):967-980. doi: 10.1016/j.ajpath.2017.12.010. Epub 2018 Jan 31.
• [3] Understanding the functional impact of copy number alterations in breast cancer using a network modeling approach.Mol Biosyst. 2016 Mar;12(3):963-72. doi: 10.1039/c5mb00655d.
• [4] Preliminary exploration of the potential of spliceosome-associated protein 130 for predicting disease severity in Crohn's disease.Ann N Y Acad Sci. 2020 Feb;1462(1):128-138. doi: 10.1111/nyas.14240. Epub 2019 Oct 3.
• [5] Circular RNA 100146 functions as an oncogene through direct binding to miR-361-3p and miR-615-5p in non-small cell lung cancer.Mol Cancer. 2019 Jan 21;18(1):13. doi: 10.1186/s12943-019-0943-0.
• [6] Mutations acquired by hepatocellular carcinoma recurrence give rise to an aggressive phenotype.Oncotarget. 2017 Apr 4;8(14):22903-22916. doi: 10.18632/oncotarget.14248.
• [7] Western diet in the perinatal period promotes dysautonomia in the offspring of adult rats.J Dev Orig Health Dis. 2017 Apr;8(2):216-225. doi: 10.1017/S2040174416000623. Epub 2016 Dec 9.
• [8] 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.
• [9] 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.
• [10] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [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] Biotinylated quercetin as an intrinsic photoaffinity proteomics probe for the identification of quercetin target proteins. Bioorg Med Chem. 2011 Aug 15;19(16):4710-20. doi: 10.1016/j.bmc.2011.07.005. Epub 2011 Jul 13.
• [13] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [14] 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.
• [15] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Identification of molecular signatures predicting the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). Toxicol Lett. 2012 Jul 7;212(1):18-28. doi: 10.1016/j.toxlet.2012.04.013. Epub 2012 May 1.