Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM6QYNQ)

• DOT Name: Cleavage and polyadenylation specificity factor subunit 6 (CPSF6)
• Synonyms: Cleavage and polyadenylation specificity factor 68 kDa subunit; CPSF 68 kDa subunit; Cleavage factor Im complex 68 kDa subunit; CFIm68; Pre-mRNA cleavage factor Im 68 kDa subunit; Protein HPBRII-4/7
• Gene Name: CPSF6
• Related Disease:
  Breast cancer
  Breast carcinoma
  Osteoarthritis
  Li-Fraumeni syndrome
  Advanced cancer
• UniProt ID: CPSF6_HUMAN
• PDB ID: 3P5T; 3P6Y; 3Q2S; 3Q2T; 4B4N; 4U0A; 4U0B; 4WYM; 6AY9; 6GX9; 7SNQ; 7ZUD; 8CL1; 8EJL
• Pfam ID: PF00076
• Sequence:
  MADGVDHIDIYADVGEEFNQEAEYGGHDQIDLYDDVISPSANNGDAPEDRDYMDTLPPTV
  GDDVGKGAAPNVVYTYTGKRIALYIGNLTWWTTDEDLTEAVHSLGVNDILEIKFFENRAN
  GQSKGFALVGVGSEASSKKLMDLLPKRELHGQNPVVTPCNKQFLSQFEMQSRKTTQSGQM
  SGEGKAGPPGGSSRAAFPQGGRGRGRFPGAVPGGDRFPGPAGPGGPPPPFPAGQTPPRPP
  LGPPGPPGPPGPPPPGQVLPPPLAGPPNRGDRPPPPVLFPGQPFGQPPLGPLPPGPPPPV
  PGYGPPPGPPPPQQGPPPPPGPFPPRPPGPLGPPLTLAPPPHLPGPPPGAPPPAPHVNPA
  FFPPPTNSGMPTSDSRGPPPTDPYGRPPPYDRGDYGPPGREMDTARTPLSEAEFEEIMNR
  NRAISSSAISRAVSDASAGDYGSAIETLVTAISLIKQSKVSADDRCKVLISSLQDCLHGI
  ESKSYGSGSRRERSRERDHSRSREKSRRHKSRSRDRHDDYYRERSRERERHRDRDRDRDR
  ERDREREYRHR
• Function: Component of the cleavage factor Im (CFIm) complex that functions as an activator of the pre-mRNA 3'-end cleavage and polyadenylation processing required for the maturation of pre-mRNA into functional mRNAs. CFIm contributes to the recruitment of multiprotein complexes on specific sequences on the pre-mRNA 3'-end, so called cleavage and polyadenylation signals (pA signals). Most pre-mRNAs contain multiple pA signals, resulting in alternative cleavage and polyadenylation (APA) producing mRNAs with variable 3'-end formation. The CFIm complex acts as a key regulator of cleavage and polyadenylation site choice during APA through its binding to 5'-UGUA-3' elements localized in the 3'-untranslated region (UTR) for a huge number of pre-mRNAs. CPSF6 enhances NUDT21/CPSF5 binding to 5'-UGUA-3' elements localized upstream of pA signals and promotes RNA looping, and hence activates directly the mRNA 3'-processing machinery. Plays a role in mRNA export ; (Microbial infection) Binds HIV-1 capsid-nucleocapsid (HIV-1 CA-NC) complexes and might thereby promote the integration of the virus in the nucleus of dividing cells (in vitro).
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway:
  Signaling by FGFR1 in disease (R-HSA-5655302)
  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)
  Signaling by cytosolic FGFR1 fusion mutants (R-HSA-1839117)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[2]
Li-Fraumeni syndrome	DISR64XA	Disputed	Biomarker	[3]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[4]

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 Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[10]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[11]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[10]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[12]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cleavage and polyadenylation specificity factor subunit 6 (CPSF6).	[11]

References

• [1] CPSF6 is a Clinically Relevant Breast Cancer Vulnerability Target: Role of CPSF6 in Breast Cancer.EBioMedicine. 2017 Jul;21:65-78. doi: 10.1016/j.ebiom.2017.06.023. Epub 2017 Jun 24.
• [2] Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019 Feb;51(2):230-236.
• [3] POSTAR: a platform for exploring post-transcriptional regulation coordinated by RNA-binding proteins.Nucleic Acids Res. 2017 Jan 4;45(D1):D104-D114. doi: 10.1093/nar/gkw888. Epub 2016 Oct 5.
• [4] Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2.Mol Cell. 2016 Feb 18;61(4):520-534. doi: 10.1016/j.molcel.2016.01.015. Epub 2016 Feb 4.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [13] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.