Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU6QXZE)

• DOT Name: Cleavage and polyadenylation specificity factor subunit 2 (CPSF2)
• Synonyms: Cleavage and polyadenylation specificity factor 100 kDa subunit; CPSF 100 kDa subunit
• Gene Name: CPSF2
• Related Disease:
  Thyroid gland papillary carcinoma
  Advanced cancer
  Neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Myopia
• UniProt ID: CPSF2_HUMAN
• PDB ID: 6URG; 6V4X
• Pfam ID: PF10996 ; PF13299 ; PF16661 ; PF07521
• Sequence:
  MTSIIKLTTLSGVQEESALCYLLQVDEFRFLLDCGWDEHFSMDIIDSLRKHVHQIDAVLL
  SHPDPLHLGALPYAVGKLGLNCAIYATIPVYKMGQMFMYDLYQSRHNTEDFTLFTLDDVD
  AAFDKIQQLKFSQIVNLKGKGHGLSITPLPAGHMIGGTIWKIVKDGEEEIVYAVDFNHKR
  EIHLNGCSLEMLSRPSLLITDSFNATYVQPRRKQRDEQLLTNVLETLRGDGNVLIAVDTA
  GRVLELAQLLDQIWRTKDAGLGVYSLALLNNVSYNVVEFSKSQVEWMSDKLMRCFEDKRN
  NPFQFRHLSLCHGLSDLARVPSPKVVLASQPDLECGFSRDLFIQWCQDPKNSIILTYRTT
  PGTLARFLIDNPSEKITEIELRKRVKLEGKELEEYLEKEKLKKEAAKKLEQSKEADIDSS
  DESDIEEDIDQPSAHKTKHDLMMKGEGSRKGSFFKQAKKSYPMFPAPEERIKWDEYGEII
  KPEDFLVPELQATEEEKSKLESGLTNGDEPMDQDLSDVPTKCISTTESIEIKARVTYIDY
  EGRSDGDSIKKIINQMKPRQLIIVHGPPEASQDLAECCRAFGGKDIKVYMPKLHETVDAT
  SETHIYQVRLKDSLVSSLQFCKAKDAELAWIDGVLDMRVSKVDTGVILEEGELKDDGEDS
  EMQVEAPSDSSVIAQQKAMKSLFGDDEKETGEESEIIPTLEPLPPHEVPGHQSVFMNEPR
  LSDFKQVLLREGIQAEFVGGVLVCNNQVAVRRTETGRIGLEGCLCQDFYRIRDLLYEQYA
  IV
• 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. Involved in the histone 3' end pre-mRNA processing.
• 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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[2]
Neoplasm	DISZKGEW	moderate	Genetic Variation	[2]
Thyroid cancer	DIS3VLDH	moderate	Biomarker	[2]
Thyroid gland carcinoma	DISMNGZ0	moderate	Biomarker	[2]
Thyroid tumor	DISLVKMD	moderate	Biomarker	[2]
Myopia	DISK5S60	Limited	Genetic Variation	[3]

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 2 (CPSF2).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Cleavage and polyadenylation specificity factor subunit 2 (CPSF2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cleavage and polyadenylation specificity factor subunit 2 (CPSF2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cleavage and polyadenylation specificity factor subunit 2 (CPSF2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cleavage and polyadenylation specificity factor subunit 2 (CPSF2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cleavage and polyadenylation specificity factor subunit 2 (CPSF2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cleavage and polyadenylation specificity factor subunit 2 (CPSF2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cleavage and polyadenylation specificity factor subunit 2 (CPSF2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cleavage and polyadenylation specificity factor subunit 2 (CPSF2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cleavage and polyadenylation specificity factor subunit 2 (CPSF2).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cleavage and polyadenylation specificity factor subunit 2 (CPSF2).	[14]

References

• [1] Negative Expression of CPSF2 Predicts a Poorer Clinical Outcome in Patients with Papillary Thyroid Carcinoma.Thyroid. 2015 Sep;25(9):1020-5. doi: 10.1089/thy.2015.0079. Epub 2015 Aug 3.
• [2] Loss of CPSF2 expression is associated with increased thyroid cancer cellular invasion and cancer stem cell population, and more aggressive disease.J Clin Endocrinol Metab. 2014 Jul;99(7):E1173-82. doi: 10.1210/jc.2013-4140. Epub 2014 Mar 21.
• [3] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [4] 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.
• [5] 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.
• [6] 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.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.