Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT53UK5L)

• DOT Name: Cleavage and polyadenylation specificity factor subunit 4 (CPSF4)
• Synonyms: Cleavage and polyadenylation specificity factor 30 kDa subunit; CPSF 30 kDa subunit; NS1 effector domain-binding protein 1; Neb-1; No arches homolog
• Gene Name: CPSF4
• Related Disease:
  Anxiety disorder
  Asthma
  Lung adenocarcinoma
  Myocardial infarction
  Paroxysmal extreme pain disorder
  Advanced cancer
  Allergic rhinitis
  Colon cancer
  Colon carcinoma
  Gastroesophageal reflux disease
  Influenza
  Lung carcinoma
  Lung neoplasm
  Neoplasm
  Colorectal carcinoma
  Breast cancer
  Breast carcinoma
  Epidermolysis bullosa simplex
  Lung cancer
  Osteoarthritis
  Type-1/2 diabetes
• UniProt ID: CPSF4_HUMAN
• PDB ID: 2D9N; 2RHK; 6DNH; 6FUW; 6URG; 6URO; 7K95; 7ZYH; 8E3I; 8E3Q
• Pfam ID: PF00642 ; PF15663 ; PF00098
• Sequence:
  MQEIIASVDHIKFDLEIAVEQQLGAQPLPFPGMDKSGAAVCEFFLKAACGKGGMCPFRHI
  SGEKTVVCKHWLRGLCKKGDQCEFLHEYDMTKMPECYFYSKFGECSNKECPFLHIDPESK
  IKDCPWYDRGFCKHGPLCRHRHTRRVICVNYLVGFCPEGPSCKFMHPRFELPMGTTEQPP
  LPQQTQPPAKQSNNPPLQRSSSLIQLTSQNSSPNQQRTPQVIGVMQSQNSSAGNRGPRPL
  EQVTCYKCGEKGHYANRCTKGHLAFLSGQ
• Function: Component of the cleavage and polyadenylation specificity factor (CPSF) complex that play a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. CPSF4 binds RNA polymers with a preference for poly(U).
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Influenza A (hsa05164)
• Reactome Pathway:
  Inhibition of Host mRNA Processing and RNA Silencing (R-HSA-168315)
  tRNA processing in the nucleus (R-HSA-6784531)
  mRNA 3'-end processing (R-HSA-72187)
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Processing of Intronless Pre-mRNAs (R-HSA-77595)
  Transport of Mature mRNA Derived from an Intronless Transcript (R-HSA-159231)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anxiety disorder	DISBI2BT	Definitive	Genetic Variation	[1]
Asthma	DISW9QNS	Definitive	Genetic Variation	[2]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[3]
Myocardial infarction	DIS655KI	Definitive	Biomarker	[4]
Paroxysmal extreme pain disorder	DISNHO6B	Definitive	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Allergic rhinitis	DIS3U9HN	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Biomarker	[9]
Influenza	DIS3PNU3	Strong	Biomarker	[10]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Lung neoplasm	DISVARNB	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Altered Expression	[12]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[8]
Breast cancer	DIS7DPX1	Limited	Biomarker	[11]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[11]
Epidermolysis bullosa simplex	DIS2CZ6X	Limited	Genetic Variation	[13]
Lung cancer	DISCM4YA	Limited	Altered Expression	[11]
Osteoarthritis	DIS05URM	Limited	Altered Expression	[14]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[15]

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 Cleavage and polyadenylation specificity factor subunit 4 (CPSF4).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cleavage and polyadenylation specificity factor subunit 4 (CPSF4).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cleavage and polyadenylation specificity factor subunit 4 (CPSF4).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cleavage and polyadenylation specificity factor subunit 4 (CPSF4).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cleavage and polyadenylation specificity factor subunit 4 (CPSF4).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cleavage and polyadenylation specificity factor subunit 4 (CPSF4).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Cleavage and polyadenylation specificity factor subunit 4 (CPSF4).	[22]

References

• [1] Prevalence and Correlates of Past-Year Recovery From DSM-5 Alcohol Use Disorder: Results From National Epidemiologic Survey on Alcohol and Related Conditions-III.Alcohol Clin Exp Res. 2019 Nov;43(11):2406-2420. doi: 10.1111/acer.14192. Epub 2019 Oct 3.
• [2] More papers, more issues.Rhinology. 2019 Feb 1;57(1):1. doi: 10.4193/Rhin19.401.
• [3] CREB-binding protein regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathway.Mol Oncol. 2016 Feb;10(2):317-29. doi: 10.1016/j.molonc.2015.10.015. Epub 2015 Nov 5.
• [4] The II genotype of the angiotensin-converting enzyme gene delays the onset of acute coronary syndromes.Arterioscler Thromb Vasc Biol. 1997 Sep;17(9):1730-3. doi: 10.1161/01.atv.17.9.1730.
• [5] Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navbeta4 peptide-mediated resurgent sodium currents.J Physiol. 2011 Feb 1;589(Pt 3):597-608. doi: 10.1113/jphysiol.2010.200915. Epub 2010 Nov 29.
• [6] Molecular mechanisms underlying mifepristone's agonistic action on ovarian cancer progression.EBioMedicine. 2019 Sep;47:170-183. doi: 10.1016/j.ebiom.2019.08.035. Epub 2019 Aug 26.
• [7] Early-Life Environmental Factors, IFN- Methylation Patterns, and Childhood Allergic Rhinitis.Int Arch Allergy Immunol. 2019;178(4):323-332. doi: 10.1159/000495304. Epub 2019 Jan 4.
• [8] Cleavage and polyadenylation specific factor 4 promotes colon cancer progression by transcriptionally activating hTERT.Biochim Biophys Acta Mol Cell Res. 2019 Oct;1866(10):1533-1543. doi: 10.1016/j.bbamcr.2019.07.001. Epub 2019 Jul 10.
• [9] Reflux episodes and esophageal impedance levels in patients with typical and atypical symptoms of gastroesophageal reflux disease.Medicine (Baltimore). 2017 Sep;96(37):e7978. doi: 10.1097/MD.0000000000007978.
• [10] The H5N1 influenza virus NS genes selected after 1998 enhance virus replication in mammalian cells.J Virol. 2007 Aug;81(15):8112-21. doi: 10.1128/JVI.00006-07. Epub 2007 May 23.
• [11] MiR-4458 inhibits breast cancer cell growth, migration, and invasiveness by targeting CPSF4.Biochem Cell Biol. 2019 Dec;97(6):722-730. doi: 10.1139/bcb-2019-0008. Epub 2019 Apr 10.
• [12] Cleavage and polyadenylation specific factor 4 targets NF-B/cyclooxygenase-2 signaling to promote lung cancer growth and progression.Cancer Lett. 2016 Oct 10;381(1):1-13. doi: 10.1016/j.canlet.2016.07.016. Epub 2016 Jul 20.
• [13] Generation and characterization of epidermolysis bullosa simplex cell lines: scratch assays show faster migration with disruptive keratin mutations.Br J Dermatol. 2003 Jul;149(1):46-58. doi: 10.1046/j.1365-2133.2003.05493.x.
• [14] The polyadenylation inhibitor cordycepin reduces pain, inflammation and joint pathology in rodent models of osteoarthritis.Sci Rep. 2019 Mar 18;9(1):4696. doi: 10.1038/s41598-019-41140-1.
• [15] Naringin attenuates liver damage in streptozotocin-induced diabetic rats.Biomed Pharmacother. 2018 Sep;105:95-102. doi: 10.1016/j.biopha.2018.05.120. Epub 2018 May 28.
• [16] 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.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] 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.
• [21] 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.
• [22] 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.