Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHHFW17)

• DOT Name: RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1)
• Synonyms: EC 3.1.3.16; TFIIF-associating CTD phosphatase
• Gene Name: CTDP1
• Related Disease:
  Congenital cataracts-facial dysmorphism-neuropathy syndrome
  Behcet disease
  Demyelinating polyneuropathy
  Marinesco-Sjogren syndrome
  Cataract
  Charcot marie tooth disease
  Lung cancer
  Lung carcinoma
  Neoplasm
• UniProt ID: CTDP1_HUMAN
• PDB ID: 1J2X; 1ONV; 2K7L
• EC Number: 3.1.3.16
• Pfam ID: PF00533 ; PF09309 ; PF03031
• Sequence:
  MEVPAAGRVPAEGAPTAAVAEVRCPGPAPLRLLEWRVAAGAAVRIGSVLAVFEAAASAQS
  SGASQSRVASGGCVRPARPERRLRSERAGVVRELCAQPGQVVAPGAVLVRLEGCSHPVVM
  KGLCAECGQDLTQLQSKNGKQQVPLSTATVSMVHSVPELMVSSEQAEQLGREDQQRLHRN
  RKLVLMVDLDQTLIHTTEQHCQQMSNKGIFHFQLGRGEPMLHTRLRPHCKDFLEKIAKLY
  ELHVFTFGSRLYAHTIAGFLDPEKKLFSHRILSRDECIDPFSKTGNLRNLFPCGDSMVCI
  IDDREDVWKFAPNLITVKKYVYFQGTGDMNAPPGSRESQTRKKVNHSRGTEVSEPSPPVR
  DPEGVTQAPGVEPSNGLEKPARELNGSEAATPRDSPRPGKPDERDIWPPAQAPTSSQELA
  GAPEPQGSCAQGGRVAPGQRPAQGATGTDLDFDLSSDSESSSESEGTKSSSSASDGESEG
  KRGRQKPKAAPEGAGALAQGSSLEPGRPAAPSLPGEAEPGAHAPDKEPELGGQEEGERDG
  LCGLGNGCADRKEAETESQNSELSGVTAGESLDQSMEEEEEEDTDEDDHLIYLEEILVRV
  HTDYYAKYDRYLNKEIEEAPDIRKIVPELKSKVLADVAIIFSGLHPTNFPIEKTREHYHA
  TALGAKILTRLVLSPDAPDRATHLIAARAGTEKVLQAQECGHLHVVNPDWLWSCLERWDK
  VEEQLFPLRDDHTKAQRENSPAAFPDREGVPPTALFHPMPVLPKAQPGPEVRIYDSNTGK
  LIRTGARGPPAPSSSLPIRQEPSSFRAVPPPQPQMFGEELPDAQDGEQPGPSRRKRQPSM
  SETMPLYTLCKEDLESMDKEVDDILGEGSDDSDSEKRRPEEQEEEPQPRKPGTRRERTLG
  APASSERSAAGGRGPRGHKRKLNEEDAASESSRESSNEDEGSSSEADEMAKALEAELNDL
  M
• Function: Processively dephosphorylates 'Ser-2' and 'Ser-5' of the heptad repeats YSPTSPS in the C-terminal domain of the largest RNA polymerase II subunit. This promotes the activity of RNA polymerase II. Plays a role in the exit from mitosis by dephosphorylating crucial mitotic substrates (USP44, CDC20 and WEE1) that are required for M-phase-promoting factor (MPF)/CDK1 inactivation.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway:
  Formation of the Early Elongation Complex (R-HSA-113418)
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of the HIV-1 Early Elongation Complex (R-HSA-167158)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Abortive elongation of HIV-1 transcript in the absence of Tat (R-HSA-167242)
  Tat-mediated HIV elongation arrest and recovery (R-HSA-167243)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  HIV elongation arrest and recovery (R-HSA-167287)
  Pausing and recovery of HIV elongation (R-HSA-167290)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital cataracts-facial dysmorphism-neuropathy syndrome	DIS277JB	Definitive	Autosomal recessive	[1]
Behcet disease	DISSYMBS	Strong	Biomarker	[2]
Demyelinating polyneuropathy	DIS7IO4W	Strong	Genetic Variation	[3]
Marinesco-Sjogren syndrome	DISKEU0B	Strong	Genetic Variation	[3]
Cataract	DISUD7SL	moderate	Genetic Variation	[1]
Charcot marie tooth disease	DIS3BT2L	Limited	CausalMutation	[4]
Lung cancer	DISCM4YA	Limited	Altered Expression	[5]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[5]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]

10 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 RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[11]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[12]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[8]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[8]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1).	[15]

References

• [1] Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome. Nat Genet. 2003 Oct;35(2):185-9. doi: 10.1038/ng1243. Epub 2003 Sep 21.
• [2] Identification of Novel Biomarkers for Behcet Disease Diagnosis Using Human Proteome Microarray Approach.Mol Cell Proteomics. 2017 Feb;16(2):147-156. doi: 10.1074/mcp.M116.061002. Epub 2016 Oct 24.
• [3] Genetic identity of Marinesco-Sjgren/myoglobinuria and CCFDN syndromes.Neurology. 2002 Jan 22;58(2):231-6. doi: 10.1212/wnl.58.2.231.
• [4] Congenital cataract facial dysmorphism neuropathy syndrome: a clinically recognizable entity.Pediatr Neurol. 2005 Oct;33(4):277-9. doi: 10.1016/j.pediatrneurol.2005.04.011.
• [5] Lentivirus-mediated knockdown of CTDP1 inhibits lung cancer cell growth in vitro.J Cancer Res Clin Oncol. 2016 Apr;142(4):723-32. doi: 10.1007/s00432-015-2070-7. Epub 2015 Nov 21.
• [6] 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.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [12] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [13] 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.
• [14] 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.
• [15] 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.