Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS3KSNG)

• DOT Name: Cleavage and polyadenylation specificity factor subunit 3 (CPSF3)
• Synonyms: EC 3.1.27.-; Cleavage and polyadenylation specificity factor 73 kDa subunit; CPSF 73 kDa subunit; mRNA 3'-end-processing endonuclease CPSF-73
• Gene Name: CPSF3
• Related Disease:
  Colorectal carcinoma
  Lung adenocarcinoma
  Neoplasm
  Non-small-cell lung cancer
  Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures
  Toxoplasmosis
• UniProt ID: CPSF3_HUMAN
• PDB ID: 2I7T; 2I7V; 6M8Q; 6V4X; 8T1Q; 8T1R
• EC Number: 3.1.27.-
• Pfam ID: PF10996 ; PF11718 ; PF16661 ; PF07521
• Sequence:
  MSAIPAEESDQLLIRPLGAGQEVGRSCIILEFKGRKIMLDCGIHPGLEGMDALPYIDLID
  PAEIDLLLISHFHLDHCGALPWFLQKTSFKGRTFMTHATKAIYRWLLSDYVKVSNISADD
  MLYTETDLEESMDKIETINFHEVKEVAGIKFWCYHAGHVLGAAMFMIEIAGVKLLYTGDF
  SRQEDRHLMAAEIPNIKPDILIIESTYGTHIHEKREEREARFCNTVHDIVNRGGRGLIPV
  FALGRAQELLLILDEYWQNHPELHDIPIYYASSLAKKCMAVYQTYVNAMNDKIRKQININ
  NPFVFKHISNLKSMDHFDDIGPSVVMASPGMMQSGLSRELFESWCTDKRNGVIIAGYCVE
  GTLAKHIMSEPEEITTMSGQKLPLKMSVDYISFSAHTDYQQTSEFIRALKPPHVILVHGE
  QNEMARLKAALIREYEDNDEVHIEVHNPRNTEAVTLNFRGEKLAKVMGFLADKKPEQGQR
  VSGILVKRNFNYHILSPCDLSNYTDLAMSTVKQTQAIPYTGPFNLLCYQLQKLTGDVEEL
  EIQEKPALKVFKNITVIQEPGMVVLEWLANPSNDMYADTVTTVILEVQSNPKIRKGAVQK
  VSKKLEMHVYSKRLEIMLQDIFGEDCVSVKDDSILSVTVDGKTANLNLETRTVECEEGSE
  DDESLREMVELAAQRLYEALTPVH
• Function: Component of the cleavage and polyadenylation specificity factor (CPSF) complex that plays 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. Has endonuclease activity, and functions as an mRNA 3'-end-processing endonuclease. Also involved in the histone 3'-end pre-mRNA processing. U7 snRNP-dependent protein that induces both the 3'-endoribonucleolytic cleavage of histone pre-mRNAs and acts as a 5' to 3' exonuclease for degrading the subsequent downstream cleavage product (DCP) of mature histone mRNAs. Cleavage occurs after the 5'-ACCCA-3' sequence in the histone pre-mRNA leaving a 3'hydroxyl group on the upstream fragment containing the stem loop (SL) and 5' phosphate on the downstream cleavage product (DCP) starting with CU nucleotides. The U7-dependent 5' to 3' exonuclease activity is processive and degrades the DCP RNA substrate even after complete removal of the U7-binding site. Binds to the downstream cleavage product (DCP) of histone pre-mRNAs and the cleaved DCP RNA substrate in a U7 snRNP dependent manner. Required for entering/progressing through S-phase of the cell cycle. Required for the selective processing of microRNAs (miRNAs) during embryonic stem cell differentiation via its interaction with ISY1. Required for the biogenesis of all miRNAs from the pri-miR-17-92 primary transcript except miR-92a. Only required for the biogenesis of miR-290 and miR-96 from the pri-miR-290-295 and pri-miR-96-183 primary transcripts, respectively.
• KEGG Pathway: mR. surveillance pathway (hsa03015)
• Reactome Pathway:
  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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[2]
Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures	DIS38GW2	Limited	Autosomal recessive	[3]
Toxoplasmosis	DISYP8FH	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cleavage and polyadenylation specificity factor subunit 3 (CPSF3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cleavage and polyadenylation specificity factor subunit 3 (CPSF3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cleavage and polyadenylation specificity factor subunit 3 (CPSF3).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cleavage and polyadenylation specificity factor subunit 3 (CPSF3).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cleavage and polyadenylation specificity factor subunit 3 (CPSF3).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cleavage and polyadenylation specificity factor subunit 3 (CPSF3).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cleavage and polyadenylation specificity factor subunit 3 (CPSF3).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Cleavage and polyadenylation specificity factor subunit 3 (CPSF3).	[10]

References

• [1] LncRNA CASC9 interacts with CPSF3 to regulate TGF- signaling in colorectal cancer.J Exp Clin Cancer Res. 2019 Jun 11;38(1):249. doi: 10.1186/s13046-019-1263-3.
• [2] CPSF3 is a promising prognostic biomarker and predicts recurrence of non-small cell lung cancer.Oncol Lett. 2019 Sep;18(3):2835-2844. doi: 10.3892/ol.2019.10659. Epub 2019 Jul 24.
• [3] Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene. Nat Commun. 2022 Feb 4;13(1):705. doi: 10.1038/s41467-022-28330-8.
• [4] Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis.EMBO Mol Med. 2017 Mar;9(3):385-394. doi: 10.15252/emmm.201607370.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [10] 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.
• [11] 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.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.