Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP151PZ)

• DOT Name: RNA polymerase-associated protein CTR9 homolog (CTR9)
• Synonyms: SH2 domain-binding protein 1
• Gene Name: CTR9
• Related Disease:
  Multiple sclerosis
  Amyotrophic lateral sclerosis
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Cervical carcinoma
  Dyschromatosis symmetrica hereditaria
  Epithelial ovarian cancer
  Frontotemporal dementia
  Gastric cancer
  Metastatic malignant neoplasm
  Neoplasm
  Ovarian cancer
  rubella
  Stomach cancer
  Warburg micro syndrome 1
  Wilms tumor
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Childhood kidney Wilms tumor
  Hereditary Wilms tumor
  Parkinsonian disorder
• UniProt ID: CTR9_HUMAN
• PDB ID: 5ZYQ; 6GMH; 6TED; 7OOP; 7OPC; 7OPD; 7UNC; 7UND
• Pfam ID: PF13374 ; PF14559 ; PF13181
• Sequence:
  MSRGSIEIPLRDTDEVIELDFDQLPEGDEVISILKQEHTQLHIWIALALEYYKQGKTEEF
  VKLLEAARIDGNLDYRDHEKDQMTCLDTLAAYYVQQARKEKNKDNKKDLITQATLLYTMA
  DKIIMYDQNHLLGRACFCLLEGDKMDQADAQFHFVLNQSPNNIPALLGKACISFNKKDYR
  GALAYYKKALRTNPGCPAEVRLGMGHCFVKLNKLEKARLAFSRALELNSKCVGALVGLAV
  LELNNKEADSIKNGVQLLSRAYTIDPSNPMVLNHLANHFFFKKDYSKVQHLALHAFHNTE
  VEAMQAESCYQLARSFHVQEDYDQAFQYYYQATQFASSSFVLPFFGLGQMYIYRGDKENA
  SQCFEKVLKAYPNNYETMKILGSLYAASEDQEKRDIAKGHLKKVTEQYPDDVEAWIELAQ
  ILEQTDIQGALSAYGTATRILQEKVQADVPPEILNNVGALHFRLGNLGEAKKYFLASLDR
  AKAEAEHDEHYYNAISVTTSYNLARLYEAMCEFHEAEKLYKNILREHPNYVDCYLRLGAM
  ARDKGNFYEASDWFKEALQINQDHPDAWSLIGNLHLAKQEWGPGQKKFERILKQPSTQSD
  TYSMLALGNVWLQTLHQPTRDREKEKRHQDRALAIYKQVLRNDAKNLYAANGIGAVLAHK
  GYFREARDVFAQVREATADISDVWLNLAHIYVEQKQYISAVQMYENCLRKFYKHQNTEVV
  LYLARALFKCGKLQECKQTLLKARHVAPSDTVLMFNVALVLQRLATSVLKDEKSNLKEVL
  NAVKELELAHRYFSYLSKVGDKMRFDLALAATEARQCSDLLSQAQYHVARARKQDEEERE
  LRAKQEQEKELLRQKLLKEQEEKRLREKEEQKKLLEQRAQYVEKTKNILMFTGETEATKE
  KKRGGGGGRRSKKGGEFDEFVNDDTDDDLPISKKKKRRKGSGSEQEGEDEEGGERKKKKR
  RRHPKGEEGSDDDETENGPKPKKRRPPKAEKKKAPKPERLPPSMKGKIKSKAIISSSDDS
  SDEDKLKIADEGHPRNSNSNSDSDEDEQRKKCASSESDSDENQNKSGSEAGSPRRPRRQR
  SDQDSDSDQPSRKRRPSGSEQSDNESVQSGRSHSGVSENDSRPASPSAESDHESERGSDN
  EGSGQGSGNESEPEGSNNEASDRGSEHGSDDSD
• Function: Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Required for mono- and trimethylation on histone H3 'Lys-4' (H3K4me3) and dimethylation on histone H3 'Lys-79' (H3K4me3). Required for Hox gene transcription. Required for the trimethylation of histone H3 'Lys-4' (H3K4me3) on genes involved in stem cell pluripotency; this function is synergistic with CXXC1 indicative for an involvement of the SET1 complex. Involved in transcriptional regulation of IL6-responsive genes and in JAK-STAT pathway; may regulate DNA-association of STAT3.
• Tissue Specificity: Widely expressed.
• Reactome Pathway:
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[1]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Dyschromatosis symmetrica hereditaria	DIS9HI9T	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Posttranslational Modification	[5]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Posttranslational Modification	[5]
rubella	DISXUI9P	Strong	Biomarker	[7]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[3]
Warburg micro syndrome 1	DIS90EI2	Strong	Biomarker	[8]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[6]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Breast cancer	DIS7DPX1	moderate	Biomarker	[10]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[10]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Genetic Variation	[6]
Hereditary Wilms tumor	DISYBXFF	Limited	Biomarker	[6]
Parkinsonian disorder	DISHGY45	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of RNA polymerase-associated protein CTR9 homolog (CTR9).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RNA polymerase-associated protein CTR9 homolog (CTR9).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of RNA polymerase-associated protein CTR9 homolog (CTR9).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of RNA polymerase-associated protein CTR9 homolog (CTR9).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA polymerase-associated protein CTR9 homolog (CTR9).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RNA polymerase-associated protein CTR9 homolog (CTR9).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of RNA polymerase-associated protein CTR9 homolog (CTR9).	[18]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of RNA polymerase-associated protein CTR9 homolog (CTR9).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RNA polymerase-associated protein CTR9 homolog (CTR9).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of RNA polymerase-associated protein CTR9 homolog (CTR9).	[21]

2 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-associated protein CTR9 homolog (CTR9).	[17]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of RNA polymerase-associated protein CTR9 homolog (CTR9).	[22]

References

• [1] The p150 subunit of dynactin (DCTN1) gene in multiple sclerosis.Acta Neurol Scand. 2007 Oct;116(4):231-4. doi: 10.1111/j.1600-0404.2007.00884.x.
• [2] ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):1041-6. doi: 10.1073/pnas.1213021110. Epub 2012 Dec 28.
• [3] p150 overexpression in gastric carcinoma: the association with p53, apoptosis and cell proliferation.Int J Cancer. 2004 Nov 10;112(3):393-8. doi: 10.1002/ijc.20443.
• [4] The adenosine deaminase acting on RNA 1 p150 isoform is involved in the pathogenesis of dyschromatosis symmetrica hereditaria.Br J Dermatol. 2013 Sep;169(3):637-44. doi: 10.1111/bjd.12401.
• [5] Promoter methylation of the SALL2 tumor suppressor gene in ovarian cancers.Mol Oncol. 2013 Jun;7(3):419-27. doi: 10.1016/j.molonc.2012.11.005. Epub 2012 Dec 12.
• [6] Identification of a novel CTR9 germline mutation in a family with Wilms tumor.Eur J Med Genet. 2018 May;61(5):294-299. doi: 10.1016/j.ejmg.2017.12.010. Epub 2017 Dec 29.
• [7] Characterization of rubella-specific humoral immunity following two doses of MMR vaccine using proteome microarray technology.PLoS One. 2017 Nov 16;12(11):e0188149. doi: 10.1371/journal.pone.0188149. eCollection 2017.
• [8] Analysis on the emerging role of Rab3 GTPase-activating protein in Warburg Micro and Martsolf syndrome.Methods Enzymol. 2008;438:131-9. doi: 10.1016/S0076-6879(07)38009-9.
• [9] Up-regulation of CHAF1A, a poor prognostic factor, facilitates cell proliferation of colon cancer.Biochem Biophys Res Commun. 2014 Jun 27;449(2):208-15. doi: 10.1016/j.bbrc.2014.05.006. Epub 2014 May 15.
• [10] Systematic identification of Ctr9 regulome in ER-positive breast cancer.BMC Genomics. 2016 Nov 9;17(1):902. doi: 10.1186/s12864-016-3248-3.
• [11] The dynactin p150 subunit: cell biology studies of sequence changes found in ALS/MND and Parkinsonian syndromes.J Neural Transm (Vienna). 2013 May;120(5):785-98. doi: 10.1007/s00702-012-0910-z. Epub 2012 Nov 11.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [22] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.