Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU39JZI)

• DOT Name: Pre-mRNA-processing-splicing factor 8 (PRPF8)
• Synonyms: 220 kDa U5 snRNP-specific protein; PRP8 homolog; Splicing factor Prp8; p220
• Gene Name: PRPF8
• Related Disease:
  Inherited retinal dystrophy
  OPTN-related open angle glaucoma
  Retinitis pigmentosa 13
  Acute myelogenous leukaemia
  Advanced cancer
  Autism spectrum disorder
  Breast cancer
  Breast carcinoma
  Cryptococcosis
  Glaucoma/ocular hypertension
  HIV infectious disease
  Influenza
  Myelodysplastic syndrome
  Neurodevelopmental disorder
  Polyarteritis nodosa
  Progressive multifocal leukoencephalopathy
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Stroke
  Vasculitis due to ADA2 deficiency
  Retinitis pigmentosa
  Autosomal dominant cerebellar ataxia type II
  Blindness
  Enhanced S-cone syndrome
  Late-onset retinal degeneration
  Leber congenital amaurosis
  Mitochondrial encephalomyopathy
  Neoplasm
• UniProt ID: PRP8_HUMAN
• PDB ID: 3E9L ; 3ENB ; 3JCR ; 3LRU ; 4JK7 ; 4JK8 ; 4JK9 ; 4JKA ; 4JKB ; 4JKC ; 4JKD ; 4JKE ; 4JKF ; 4JKG ; 4JKH ; 4KIT ; 5MQF ; 5O9Z ; 5XJC ; 5YZG ; 5Z56 ; 5Z57 ; 5Z58 ; 6AH0 ; 6AHD ; 6FF4 ; 6FF7 ; 6ICZ ; 6ID0 ; 6ID1 ; 6QDV ; 6QW6 ; 6QX9 ; 6S8Q ; 6S9I ; 6ZYM ; 7A5P ; 7AAV ; 7ABF ; 7ABG ; 7ABI ; 7BDI ; 7BDJ ; 7BDK ; 7BDL ; 7DVQ ; 7OS2 ; 7PJH ; 7PX3 ; 7QTT ; 7W59 ; 7W5A ; 7W5B ; 8BC8 ; 8BC9 ; 8BCA ; 8BCB ; 8BCC ; 8BCD ; 8BCE ; 8BCF ; 8BCG ; 8C6J ; 8CH6
• Pfam ID: PF01398 ; PF08082 ; PF08083 ; PF08084 ; PF12134 ; PF10598 ; PF10597 ; PF10596
• Sequence:
  MAGVFPYRGPGNPVPGPLAPLPDYMSEEKLQEKARKWQQLQAKRYAEKRKFGFVDAQKED
  MPPEHVRKIIRDHGDMTNRKFRHDKRVYLGALKYMPHAVLKLLENMPMPWEQIRDVPVLY
  HITGAISFVNEIPWVIEPVYISQWGSMWIMMRREKRDRRHFKRMRFPPFDDEEPPLDYAD
  NILDVEPLEAIQLELDPEEDAPVLDWFYDHQPLRDSRKYVNGSTYQRWQFTLPMMSTLYR
  LANQLLTDLVDDNYFYLFDLKAFFTSKALNMAIPGGPKFEPLVRDINLQDEDWNEFNDIN
  KIIIRQPIRTEYKIAFPYLYNNLPHHVHLTWYHTPNVVFIKTEDPDLPAFYFDPLINPIS
  HRHSVKSQEPLPDDDEEFELPEFVEPFLKDTPLYTDNTANGIALLWAPRPFNLRSGRTRR
  ALDIPLVKNWYREHCPAGQPVKVRVSYQKLLKYYVLNALKHRPPKAQKKRYLFRSFKATK
  FFQSTKLDWVEVGLQVCRQGYNMLNLLIHRKNLNYLHLDYNFNLKPVKTLTTKERKKSRF
  GNAFHLCREVLRLTKLVVDSHVQYRLGNVDAFQLADGLQYIFAHVGQLTGMYRYKYKLMR
  QIRMCKDLKHLIYYRFNTGPVGKGPGCGFWAAGWRVWLFFMRGITPLLERWLGNLLARQF
  EGRHSKGVAKTVTKQRVESHFDLELRAAVMHDILDMMPEGIKQNKARTILQHLSEAWRCW
  KANIPWKVPGLPTPIENMILRYVKAKADWWTNTAHYNRERIRRGATVDKTVCKKNLGRLT
  RLYLKAEQERQHNYLKDGPYITAEEAVAVYTTTVHWLESRRFSPIPFPPLSYKHDTKLLI
  LALERLKEAYSVKSRLNQSQREELGLIEQAYDNPHEALSRIKRHLLTQRAFKEVGIEFMD
  LYSHLVPVYDVEPLEKITDAYLDQYLWYEADKRRLFPPWIKPADTEPPPLLVYKWCQGIN
  NLQDVWETSEGECNVMLESRFEKMYEKIDLTLLNRLLRLIVDHNIADYMTAKNNVVINYK
  DMNHTNSYGIIRGLQFASFIVQYYGLVMDLLVLGLHRASEMAGPPQMPNDFLSFQDIATE
  AAHPIRLFCRYIDRIHIFFRFTADEARDLIQRYLTEHPDPNNENIVGYNNKKCWPRDARM
  RLMKHDVNLGRAVFWDIKNRLPRSVTTVQWENSFVSVYSKDNPNLLFNMCGFECRILPKC
  RTSYEEFTHKDGVWNLQNEVTKERTAQCFLRVDDESMQRFHNRVRQILMASGSTTFTKIV
  NKWNTALIGLMTYFREAVVNTQELLDLLVKCENKIQTRIKIGLNSKMPSRFPPVVFYTPK
  ELGGLGMLSMGHVLIPQSDLRWSKQTDVGITHFRSGMSHEEDQLIPNLYRYIQPWESEFI
  DSQRVWAEYALKRQEAIAQNRRLTLEDLEDSWDRGIPRINTLFQKDRHTLAYDKGWRVRT
  DFKQYQVLKQNPFWWTHQRHDGKLWNLNNYRTDMIQALGGVEGILEHTLFKGTYFPTWEG
  LFWEKASGFEESMKWKKLTNAQRSGLNQIPNRRFTLWWSPTINRANVYVGFQVQLDLTGI
  FMHGKIPTLKISLIQIFRAHLWQKIHESIVMDLCQVFDQELDALEIETVQKETIHPRKSY
  KMNSSCADILLFASYKWNVSRPSLLADSKDVMDSTTTQKYWIDIQLRWGDYDSHDIERYA
  RAKFLDYTTDNMSIYPSPTGVLIAIDLAYNLHSAYGNWFPGSKPLIQQAMAKIMKANPAL
  YVLRERIRKGLQLYSSEPTEPYLSSQNYGELFSNQIIWFVDDTNVYRVTIHKTFEGNLTT
  KPINGAIFIFNPRTGQLFLKIIHTSVWAGQKRLGQLAKWKTAEEVAALIRSLPVEEQPKQ
  IIVTRKGMLDPLEVHLLDFPNIVIKGSELQLPFQACLKVEKFGDLILKATEPQMVLFNLY
  DDWLKTISSYTAFSRLILILRALHVNNDRAKVILKPDKTTITEPHHIWPTLTDEEWIKVE
  VQLKDLILADYGKKNNVNVASLTQSEIRDIILGMEISAPSQQRQQIAEIEKQTKEQSQLT
  ATQTRTVNKHGDEIITSTTSNYETQTFSSKTEWRVRAISAANLHLRTNHIYVSSDDIKET
  GYTYILPKNVLKKFICISDLRAQIAGYLYGVSPPDNPQVKEIRCIVMVPQWGTHQTVHLP
  GQLPQHEYLKEMEPLGWIHTQPNESPQLSPQDVTTHAKIMADNPSWDGEKTIIITCSFTP
  GSCTLTAYKLTPSGYEWGRQNTDKGNNPKGYLPSHYERVQMLLSDRFLGFFMVPAQSSWN
  YNFMGVRHDPNMKYELQLANPKEFYHEVHRPSHFLNFALLQEGEVYSADREDLYA
• Function: Plays a role in pre-mRNA splicing as core component of precatalytic, catalytic and postcatalytic spliceosomal complexes, both of the predominant U2-type spliceosome and the minor U12-type spliceosome. Functions as a scaffold that mediates the ordered assembly of spliceosomal proteins and snRNAs. Required for the assembly of the U4/U6-U5 tri-snRNP complex, a building block of the spliceosome. Functions as a scaffold that positions spliceosomal U2, U5 and U6 snRNAs at splice sites on pre-mRNA substrates, so that splicing can occur. Interacts with both the 5' and the 3' splice site.
• Tissue Specificity: Widely expressed.
• 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

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited retinal dystrophy	DISGGL77	Definitive	Autosomal dominant	[1]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Genetic Variation	[2]
Retinitis pigmentosa 13	DISXKU6Y	Definitive	Autosomal dominant	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[8]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Genetic Variation	[2]
HIV infectious disease	DISO97HC	Strong	Biomarker	[9]
Influenza	DIS3PNU3	Strong	Altered Expression	[10]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[11]
Neurodevelopmental disorder	DIS372XH	Strong	Autosomal dominant	[12]
Polyarteritis nodosa	DISRQ5X8	Strong	Biomarker	[7]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Altered Expression	[13]
Prostate cancer	DISF190Y	Strong	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[13]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[14]
Stroke	DISX6UHX	Strong	Biomarker	[15]
Vasculitis due to ADA2 deficiency	DIS1UHPY	Strong	Biomarker	[7]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[16]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Limited	Genetic Variation	[17]
Blindness	DISTIM10	Limited	Genetic Variation	[18]
Enhanced S-cone syndrome	DIS2IWS3	Limited	Genetic Variation	[17]
Late-onset retinal degeneration	DIST9GP4	Limited	Genetic Variation	[17]
Leber congenital amaurosis	DISMGH8F	Limited	Genetic Variation	[17]
Mitochondrial encephalomyopathy	DISA6PTN	Limited	Genetic Variation	[17]
Neoplasm	DISZKGEW	Limited	Biomarker	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Pre-mRNA-processing-splicing factor 8 (PRPF8).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Pre-mRNA-processing-splicing factor 8 (PRPF8).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pre-mRNA-processing-splicing factor 8 (PRPF8).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Pre-mRNA-processing-splicing factor 8 (PRPF8).	[24]
Marinol	DM70IK5	Approved	Marinol increases the expression of Pre-mRNA-processing-splicing factor 8 (PRPF8).	[25]
Selenium	DM25CGV	Approved	Selenium increases the expression of Pre-mRNA-processing-splicing factor 8 (PRPF8).	[26]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Pre-mRNA-processing-splicing factor 8 (PRPF8).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Pre-mRNA-processing-splicing factor 8 (PRPF8).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Pre-mRNA-processing-splicing factor 8 (PRPF8).	[30]
ORG2058	DMH1M6N	Investigative	ORG2058 decreases the expression of Pre-mRNA-processing-splicing factor 8 (PRPF8).	[31]

2 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 Pre-mRNA-processing-splicing factor 8 (PRPF8).	[23]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Pre-mRNA-processing-splicing factor 8 (PRPF8).	[29]

References

• [1] 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.
• [2] Variants in the PRPF8 Gene are Associated with Glaucoma.Mol Neurobiol. 2018 May;55(5):4504-4510. doi: 10.1007/s12035-017-0673-5. Epub 2017 Jul 13.
• [3] 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.
• [4] Mutations in Splicing Factor Genes in Myeloid Malignancies: Significance and Impact on Clinical Features.Cancers (Basel). 2019 Nov 22;11(12):1844. doi: 10.3390/cancers11121844.
• [5] Prp8 regulates oncogene-induced hyperplastic growth in Drosophila.Development. 2018 Nov 12;145(22):dev162156. doi: 10.1242/dev.162156.
• [6] Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort.Autism Res. 2020 Feb;13(2):199-206. doi: 10.1002/aur.2238. Epub 2019 Nov 6.
• [7] Mutational landscape of RNA-binding proteins in human cancers.RNA Biol. 2018 Jan 2;15(1):115-129. doi: 10.1080/15476286.2017.1391436. Epub 2017 Nov 14.
• [8] Spliceosomal Prp8 intein at the crossroads of protein and RNA splicing.PLoS Biol. 2019 Oct 10;17(10):e3000104. doi: 10.1371/journal.pbio.3000104. eCollection 2019 Oct.
• [9] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [10] Influenza A virus upregulates PRPF8 gene expression to increase virus production.Arch Virol. 2017 May;162(5):1223-1235. doi: 10.1007/s00705-016-3210-3. Epub 2017 Jan 21.
• [11] Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells.Leukemia. 2015 May;29(5):1092-103. doi: 10.1038/leu.2014.331. Epub 2014 Nov 27.
• [12] 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.
• [13] Specific expression of lncRNA RP13-650J16.1 and TCONS_00023979 in prostate cancer.Biosci Rep. 2018 Oct 31;38(5):BSR20171571. doi: 10.1042/BSR20171571. Print 2018 Oct 31.
• [14] ARP2 a novel protein involved in apoptosis of LNCaP cells shares a high degree homology with splicing factor Prp8.Mol Cell Biochem. 2005 Jan;269(1-2):189-201. doi: 10.1007/s11010-005-3084-2.
• [15] Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.Nat Genet. 2018 Apr;50(4):524-537. doi: 10.1038/s41588-018-0058-3. Epub 2018 Mar 12.
• [16] 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.
• [17] Histopathologic-genotypic correlations in retinitis pigmentosa and allied diseases.Ophthalmic Genet. 2005 Jun;26(2):91-100. doi: 10.1080/13816810590968032.
• [18] Prp8 retinitis pigmentosa mutants cause defects in the transition between the catalytic steps of splicing.RNA. 2016 May;22(5):793-809. doi: 10.1261/rna.055459.115. Epub 2016 Mar 11.
• [19] PRPF8 defects cause missplicing in myeloid malignancies.Leukemia. 2015 Jan;29(1):126-36. doi: 10.1038/leu.2014.144. Epub 2014 Apr 30.
• [20] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [21] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [22] 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.
• [23] Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure. Environ Health Perspect. 2020 Jun;128(6):67015. doi: 10.1289/EHP6263. Epub 2020 Jun 30.
• [24] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [25] 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.
• [26] 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.
• [27] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [28] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [29] 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.
• [30] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [31] The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5. Mol Endocrinol. 2010 Jul;24(7):1380-92. doi: 10.1210/me.2009-0516. Epub 2010 Jun 2.