Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAU1KOM)

• DOT Name: Cleavage and polyadenylation specificity factor subunit 1 (CPSF1)
• Synonyms: Cleavage and polyadenylation specificity factor 160 kDa subunit; CPSF 160 kDa subunit
• Gene Name: CPSF1
• Related Disease:
  Disorder of orbital region
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Myopia 27
  Lung cancer
  Lung carcinoma
  Neoplasm
• UniProt ID: CPSF1_HUMAN
• PDB ID: 6BLY; 6BM0; 6DNH; 6F9N; 6FUW; 6URG; 6URO; 8E3I; 8E3Q
• Pfam ID: PF03178 ; PF10433
• Sequence:
  MYAVYKQAHPPTGLEFSMYCNFFNNSERNLVVAGTSQLYVYRLNRDAEALTKNDRSTEGK
  AHREKLELAASFSFFGNVMSMASVQLAGAKRDALLLSFKDAKLSVVEYDPGTHDLKTLSL
  HYFEEPELRDGFVQNVHTPRVRVDPDGRCAAMLVYGTRLVVLPFRRESLAEEHEGLVGEG
  QRSSFLPSYIIDVRALDEKLLNIIDLQFLHGYYEPTLLILFEPNQTWPGRVAVRQDTCSI
  VAISLNITQKVHPVIWSLTSLPFDCTQALAVPKPIGGVVVFAVNSLLYLNQSVPPYGVAL
  NSLTTGTTAFPLRTQEGVRITLDCAQATFISYDKMVISLKGGEIYVLTLITDGMRSVRAF
  HFDKAAASVLTTSMVTMEPGYLFLGSRLGNSLLLKYTEKLQEPPASAVREAADKEEPPSK
  KKRVDATAGWSAAGKSVPQDEVDEIEVYGSEAQSGTQLATYSFEVCDSILNIGPCANAAV
  GEPAFLSEEFQNSPEPDLEIVVCSGHGKNGALSVLQKSIRPQVVTTFELPGCYDMWTVIA
  PVRKEEEDNPKGEGTEQEPSTTPEADDDGRRHGFLILSREDSTMILQTGQEIMELDTSGF
  ATQGPTVFAGNIGDNRYIVQVSPLGIRLLEGVNQLHFIPVDLGAPIVQCAVADPYVVIMS
  AEGHVTMFLLKSDSYGGRHHRLALHKPPLHHQSKVITLCLYRDLSGMFTTESRLGGARDE
  LGGRSGPEAEGLGSETSPTVDDEEEMLYGDSGSLFSPSKEEARRSSQPPADRDPAPFRAE
  PTHWCLLVRENGTMEIYQLPDWRLVFLVKNFPVGQRVLVDSSFGQPTTQGEARREEATRQ
  GELPLVKEVLLVALGSRQSRPYLLVHVDQELLIYEAFPHDSQLGQGNLKVRFKKVPHNIN
  FREKKPKPSKKKAEGGGAEEGAGARGRVARFRYFEDIYGYSGVFICGPSPHWLLVTGRGA
  LRLHPMAIDGPVDSFAPFHNVNCPRGFLYFNRQGELRISVLPAYLSYDAPWPVRKIPLRC
  TAHYVAYHVESKVYAVATSTNTPCARIPRMTGEEKEFETIERDERYIHPQQEAFSIQLIS
  PVSWEAIPNARIELQEWEHVTCMKTVSLRSEETVSGLKGYVAAGTCLMQGEEVTCRGRIL
  IMDVIEVVPEPGQPLTKNKFKVLYEKEQKGPVTALCHCNGHLVSAIGQKIFLWSLRASEL
  TGMAFIDTQLYIHQMISVKNFILAADVMKSISLLRYQEESKTLSLVSRDAKPLEVYSVDF
  MVDNAQLGFLVSDRDRNLMVYMYLPEAKESFGGMRLLRRADFHVGAHVNTFWRTPCRGAT
  EGLSKKSVVWENKHITWFATLDGGIGLLLPMQEKTYRRLLMLQNALTTMLPHHAGLNPRA
  FRMLHVDRRTLQNAVRNVLDGELLNRYLYLSTMERSELAKKIGTTPDIILDDLLETDRVT
  AHF
• 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. This subunit is involved in the RNA recognition step of the polyadenylation reaction. May play a role in eye morphogenesis and the development of retinal ganglion cell projections to the midbrain.
• Tissue Specificity: Widely expressed, with high expression in the retina.
• KEGG Pathway: mR. surveillance pathway (hsa03015)
• Reactome Pathway:
  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

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Disorder of orbital region	DISH0ECJ	Strong	Genetic Variation	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[2]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[2]
Myopia 27	DIS22GSR	Strong	Autosomal dominant	[1]
Lung cancer	DISCM4YA	Limited	Altered Expression	[3]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[3]
Neoplasm	DISZKGEW	Limited	Altered Expression	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Cleavage and polyadenylation specificity factor subunit 1 (CPSF1) affects the response to substance of Methotrexate.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cleavage and polyadenylation specificity factor subunit 1 (CPSF1).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Cleavage and polyadenylation specificity factor subunit 1 (CPSF1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cleavage and polyadenylation specificity factor subunit 1 (CPSF1).	[5]
Selenium	DM25CGV	Approved	Selenium increases the expression of Cleavage and polyadenylation specificity factor subunit 1 (CPSF1).	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Cleavage and polyadenylation specificity factor subunit 1 (CPSF1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cleavage and polyadenylation specificity factor subunit 1 (CPSF1).	[8]
Pyrrolidine dithiocarbamate	DM5ZAS6	Investigative	Pyrrolidine dithiocarbamate increases the expression of Cleavage and polyadenylation specificity factor subunit 1 (CPSF1).	[9]

References

• [1] CPSF1 mutations are associated with early-onset high myopia and involved in retinal ganglion cell axon projection. Hum Mol Genet. 2019 Jun 15;28(12):1959-1970. doi: 10.1093/hmg/ddz029.
• [2] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [3] Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer.Sci Rep. 2017 Jun 20;7(1):3896. doi: 10.1038/s41598-017-04248-w.
• [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] 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.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] 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.
• [8] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [9] Effects of a redox-active agent on lymphocyte activation and early gene expression patterns. Free Radic Biol Med. 2004 Nov 15;37(10):1550-63.
• [10] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.