Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT22MEO6)

• DOT Name: Pre-mRNA-splicing factor CWC22 homolog (CWC22)
• Synonyms: Nucampholin homolog; fSAPb
• Gene Name: CWC22
• Related Disease:
  Colitis
  Polyneuropathy
  Schizophrenia
  Neoplasm
  Parkinson disease
• UniProt ID: CWC22_HUMAN
• PDB ID: 4C9B; 5MQF; 5XJC; 5YZG; 5Z56; 5Z57; 5Z58; 6FF7; 6ICZ; 6QDV; 6YVH; 6ZYM; 7A5P; 7DVQ; 7QTT; 7W59; 7W5A; 7W5B; 8C6J; 8CH6
• Pfam ID: PF02847 ; PF02854
• Sequence:
  MKSSVAQIKPSSGHDRRENLNSYQRNSSPEDRYEEQERSPRDRDYFDYSRSDYEHSRRGR
  SYDSSMESRNRDREKRRERERDTDRKRSRKSPSPGRRNPETSVTQSSSAQDEPATKKKKD
  ELDPLLTRTGGAYIPPAKLRMMQEQITDKNSLAYQRMSWEALKKSINGLINKVNISNISI
  IIQELLQENIVRGRGLLSRSVLQAQSASPIFTHVYAALVAIINSKFPQIGELILKRLILN
  FRKGYRRNDKQLCLTASKFVAHLINQNVAHEVLCLEMLTLLLERPTDDSVEVAIGFLKEC
  GLKLTQVSPRGINAIFERLRNILHESEIDKRVQYMIEVMFAVRKDGFKDHPIILEGLDLV
  EEDDQFTHMLPLEDDYNPEDVLNVFKMDPNFMENEEKYKAIKKEILDEGDTDSNTDQDAG
  SSEEDEEEEEEEGEEDEEGQKVTIHDKTEINLVSFRRTIYLAIQSSLDFEECAHKLLKME
  FPESQTKELCNMILDCCAQQRTYEKFFGLLAGRFCMLKKEYMESFEGIFKEQYDTIHRLE
  TNKLRNVAKMFAHLLYTDSLPWSVLECIKLSEETTTSSSRIFVKIFFQELCEYMGLPKLN
  ARLKDETLQPFFEGLLPRDNPRNTRFAINFFTSIGLGGLTDELREHLKNTPKVIVAQKPD
  VEQNKSSPSSSSSASSSSESDSSDSDSDSSDSSSESSSEESDSSSISSHSSASANDVRKK
  GHGKTRSKEVDKLIRNQQTNDRKQKERRQEHGHQETRTERERRSEKHRDQNSSGSNWRDP
  ITKYTSDKDVPSERNNYSRVANDRDQEMHIDLENKHGDPKKKRGERRNSFSENEKHTHRI
  KDSENFRRKDRSKSKEMNRKHSGSRSDEDRYQNGAERRWEKSSRYSEQSRESKKNQDRRR
  EKSPAKQK
• Function: Required for pre-mRNA splicing as component of the spliceosome. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable). Promotes exon-junction complex (EJC) assembly. Hinders EIF4A3 from non-specifically binding RNA and escorts it to the splicing machinery to promote EJC assembly on mature mRNAs. Through its role in EJC assembly, required for nonsense-mediated mRNA decay.
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colitis	DISAF7DD	Strong	Biomarker	[1]
Polyneuropathy	DISB9G3W	Strong	Altered Expression	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	moderate	Biomarker	[4]
Parkinson disease	DISQVHKL	Limited	Biomarker	[5]

4 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 Pre-mRNA-splicing factor CWC22 homolog (CWC22).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Pre-mRNA-splicing factor CWC22 homolog (CWC22).	[8]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Pre-mRNA-splicing factor CWC22 homolog (CWC22).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Pre-mRNA-splicing factor CWC22 homolog (CWC22).	[13]

4 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 Pre-mRNA-splicing factor CWC22 homolog (CWC22).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Pre-mRNA-splicing factor CWC22 homolog (CWC22).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Pre-mRNA-splicing factor CWC22 homolog (CWC22).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pre-mRNA-splicing factor CWC22 homolog (CWC22).	[12]

References

• [1] Actin related protein 3 (ARP3) promotes apoptosis of intestinal epithelial cells in ulcerative colitis.Pathol Res Pract. 2019 Feb;215(2):235-242. doi: 10.1016/j.prp.2018.10.011. Epub 2018 Oct 24.
• [2] Diabetic polyneuropathy, sensory neurons, nuclear structure and spliceosome alterations: a role for CWC22.Dis Model Mech. 2017 Mar 1;10(3):215-224. doi: 10.1242/dmm.028225.
• [3] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [4] Intracellular Chloride Ion Channel Protein-1 Expression in Clear Cell Renal Cell Carcinoma.Cancer Genomics Proteomics. 2019 Jul-Aug;16(4):299-307. doi: 10.21873/cgp.20135.
• [5] A high-efficiency induction of dopaminergic cells from human umbilical mesenchymal stem cells for the treatment of hemiparkinsonian rats.Cell Transplant. 2015;24(11):2251-62. doi: 10.3727/096368914X685078. Epub 2014 Oct 6.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [10] 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.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [13] 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.