Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ1STV3)

• DOT Name: Pre-mRNA-processing factor 19 (PRPF19)
• Synonyms: EC 2.3.2.27; Nuclear matrix protein 200; PRP19/PSO4 homolog; hPso4; RING-type E3 ubiquitin transferase PRP19; Senescence evasion factor
• Gene Name: PRPF19
• Related Disease:
  Alzheimer disease
  Breast neoplasm
  Gastric cancer
  Gastric neoplasm
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Lung adenocarcinoma
  Neoplasm
  Werner syndrome
  Asthma
• UniProt ID: PRP19_HUMAN
• PDB ID: 4LG8; 5MQF; 5XJC; 5YZG; 5Z56; 5Z57; 6FF7; 6ICZ; 6ID0; 6ID1; 6QDV; 7A5P; 7W59; 7W5A; 7W5B; 8C6J; 8CH6
• EC Number: 2.3.2.27
• Pfam ID: PF08606 ; PF04564 ; PF00400
• Sequence:
  MSLICSISNEVPEHPCVSPVSNHVYERRLIEKYIAENGTDPINNQPLSEEQLIDIKVAHP
  IRPKPPSATSIPAILKALQDEWDAVMLHSFTLRQQLQTTRQELSHALYQHDAACRVIARL
  TKEVTAAREALATLKPQAGLIVPQAVPSSQPSVVGAGEPMDLGELVGMTPEIIQKLQDKA
  TVLTTERKKRGKTVPEELVKPEELSKYRQVASHVGLHSASIPGILALDLCPSDTNKILTG
  GADKNVVVFDKSSEQILATLKGHTKKVTSVVFHPSQDLVFSASPDATIRIWSVPNASCVQ
  VVRAHESAVTGLSLHATGDYLLSSSDDQYWAFSDIQTGRVLTKVTDETSGCSLTCAQFHP
  DGLIFGTGTMDSQIKIWDLKERTNVANFPGHSGPITSIAFSENGYYLATAADDSSVKLWD
  LRKLKNFKTLQLDNNFEVKSLIFDQSGTYLALGGTDVQIYICKQWTEILHFTEHSGLTTG
  VAFGHHAKFIASTGMDRSLKFYSL
• Function: Ubiquitin-protein ligase which is a core component of several complexes mainly involved pre-mRNA splicing and DNA repair. Required for pre-mRNA splicing as component of the spliceosome. Core component of the PRP19C/Prp19 complex/NTC/Nineteen complex which is part of the spliceosome and participates in its assembly, its remodeling and is required for its activity. During assembly of the spliceosome, mediates 'Lys-63'-linked polyubiquitination of the U4 spliceosomal protein PRPF3. Ubiquitination of PRPF3 allows its recognition by the U5 component PRPF8 and stabilizes the U4/U5/U6 tri-snRNP spliceosomal complex. Recruited to RNA polymerase II C-terminal domain (CTD) and the pre-mRNA, it may also couple the transcriptional and spliceosomal machineries. The XAB2 complex, which contains PRPF19, is also involved in pre-mRNA splicing, transcription and transcription-coupled repair. Beside its role in pre-mRNA splicing PRPF19, as part of the PRP19-CDC5L complex, plays a role in the DNA damage response/DDR. It is recruited to the sites of DNA damage by the RPA complex where PRPF19 directly ubiquitinates RPA1 and RPA2. 'Lys-63'-linked polyubiquitination of the RPA complex allows the recruitment of the ATR-ATRIP complex and the activation of ATR, a master regulator of the DNA damage response. May also play a role in DNA double-strand break (DSB) repair by recruiting the repair factor SETMAR to altered DNA. As part of the PSO4 complex may also be involved in the DNA interstrand cross-links/ICLs repair process. In addition, may also mediate 'Lys-48'-linked polyubiquitination of substrates and play a role in proteasomal degradation. May play a role in the biogenesis of lipid droplets. May play a role in neural differentiation possibly through its function as part of the spliceosome.
• Tissue Specificity: Ubiquitous. Weakly expressed in senescent cells of different tissue origins. Highly expressed in tumor cell lines.
• KEGG Pathway:
  Spliceosome (hsa03040)
  Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  mRNA Splicing - Major Pathway (R-HSA-72163)
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Werner syndrome	DISZY45W	moderate	Biomarker	[6]
Asthma	DISW9QNS	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cidofovir	DMA13GD	Approved	Pre-mRNA-processing factor 19 (PRPF19) increases the Apoptosis ADR of Cidofovir.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Pre-mRNA-processing factor 19 (PRPF19).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pre-mRNA-processing factor 19 (PRPF19).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pre-mRNA-processing factor 19 (PRPF19).	[10]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Pre-mRNA-processing factor 19 (PRPF19).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Pre-mRNA-processing factor 19 (PRPF19).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Pre-mRNA-processing factor 19 (PRPF19).	[13]

References

• [1] PrP-grafted antibodies bind certain amyloid -protein aggregates, but do not prevent toxicity.Brain Res. 2019 May 1;1710:125-135. doi: 10.1016/j.brainres.2018.12.038. Epub 2018 Dec 26.
• [2] SNEV overexpression extends the life span of human endothelial cells.Exp Cell Res. 2006 Apr 1;312(6):746-59. doi: 10.1016/j.yexcr.2005.11.025. Epub 2006 Jan 4.
• [3] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [4] Prp19 Arrests Cell Cycle via Cdc5L in Hepatocellular Carcinoma Cells.Int J Mol Sci. 2017 Apr 7;18(4):778. doi: 10.3390/ijms18040778.
• [5] PRP19 upregulation inhibits cell proliferation in lung adenocarcinomas by p21-mediated induction of cell cycle arrest.Biomed Pharmacother. 2014 May;68(4):463-70. doi: 10.1016/j.biopha.2014.03.006. Epub 2014 Mar 18.
• [6] The Pso4 mRNA splicing and DNA repair complex interacts with WRN for processing of DNA interstrand cross-links.J Biol Chem. 2005 Dec 9;280(49):40559-67. doi: 10.1074/jbc.M508453200. Epub 2005 Oct 12.
• [7] Evaluation of a partial genome screening of two asthma susceptibility regions using bayesian network based bayesian multilevel analysis of relevance.PLoS One. 2012;7(3):e33573. doi: 10.1371/journal.pone.0033573. Epub 2012 Mar 14.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [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] 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.
• [12] 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.
• [13] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [14] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.