Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT98OJ42)

• DOT Name: CCR4-NOT transcription complex subunit 2 (CNOT2)
• Synonyms: CCR4-associated factor 2
• Gene Name: CNOT2
• Related Disease:
  Neoplasm
  Adult lymphoma
  Dengue
  Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies
  Lung cancer
  Lymphoma
  Ovarian neoplasm
  Pediatric lymphoma
• UniProt ID: CNOT2_HUMAN
• PDB ID: 4C0D; 4C0F; 5FU6; 5FU7
• Pfam ID: PF04153
• Sequence:
  MVRTDGHTLSEKRNYQVTNSMFGASRKKFVEGVDSDYHDENMYYSQSSMFPHRSEKDMLA
  SPSTSGQLSQFGASLYGQQSALGLPMRGMSNNTPQLNRSLSQGTQLPSHVTPTTGVPTMS
  LHTPPSPSRGILPMNPRNMMNHSQVGQGIGIPSRTNSMSSSGLGSPNRSSPSIICMPKQQ
  PSRQPFTVNSMSGFGMNRNQAFGMNNSLSSNIFNGTDGSENVTGLDLSDFPALADRNRRE
  GSGNPTPLINPLAGRAPYVGMVTKPANEQSQDFSIHNEDFPALPGSSYKDPTSSNDDSKS
  NLNTSGKTTSSTDGPKFPGDKSSTTQNNNQQKKGIQVLPDGRVTNIPQGMVTDQFGMIGL
  LTFIRAAETDPGMVHLALGSDLTTLGLNLNSPENLYPKFASPWASSPCRPQDIDFHVPSE
  YLTNIHIRDKLAAIKLGRYGEDLLFYLYYMNGGDVLQLLAAVELFNRDWRYHKEERVWIT
  RAPGMEPTMKTNTYERGTYYFFDCLNWRKVAKEFHLEYDKLEERPHLPSTFNYNPAQQAF
• Function: Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Required for the CCR4-NOT complex structural integrity. Can repress transcription and may link the CCR4-NOT complex to transcriptional regulation; the repressive function may specifically involve the N-Cor repressor complex containing HDAC3, NCOR1 and NCOR2. Involved in the maintenance of embryonic stem (ES) cell identity.
• Tissue Specificity: Ubiquitous. Highly expressed in brain, heart, thymus, spleen, kidney, liver, small intestine, placenta, lung and peripheral blood leukocytes.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway:
  TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain (R-HSA-6804115)
  M-decay (R-HSA-9820841)
  Deadenylation of mRNA (R-HSA-429947)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[2]
Dengue	DISKH221	Strong	Biomarker	[3]
Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies	DISZZHB0	Strong	Autosomal dominant	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[2]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[6]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[2]

4 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 CCR4-NOT transcription complex subunit 2 (CNOT2).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of CCR4-NOT transcription complex subunit 2 (CNOT2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of CCR4-NOT transcription complex subunit 2 (CNOT2).	[14]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of CCR4-NOT transcription complex subunit 2 (CNOT2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of CCR4-NOT transcription complex subunit 2 (CNOT2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CCR4-NOT transcription complex subunit 2 (CNOT2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of CCR4-NOT transcription complex subunit 2 (CNOT2).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of CCR4-NOT transcription complex subunit 2 (CNOT2).	[11]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of CCR4-NOT transcription complex subunit 2 (CNOT2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of CCR4-NOT transcription complex subunit 2 (CNOT2).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of CCR4-NOT transcription complex subunit 2 (CNOT2).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of CCR4-NOT transcription complex subunit 2 (CNOT2).	[17]
Manganese	DMKT129	Investigative	Manganese decreases the expression of CCR4-NOT transcription complex subunit 2 (CNOT2).	[19]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the expression of CCR4-NOT transcription complex subunit 2 (CNOT2).	[20]

References

• [1] An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease.Genome Res. 2014 Feb;24(2):227-40. doi: 10.1101/gr.166223.113. Epub 2013 Dec 9.
• [2] The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people.HIV Med. 2018 Feb;19(2):90-101. doi: 10.1111/hiv.12546. Epub 2017 Aug 31.
• [3] CNOT2 facilitates dengue virus infection via negatively modulating IFN-Independent Non-Canonical JAK/STAT pathway.Biochem Biophys Res Commun. 2019 Jul 30;515(3):403-409. doi: 10.1016/j.bbrc.2019.05.083. Epub 2019 May 31.
• [4] Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat Genet. 2017 Apr;49(4):504-510. doi: 10.1038/ng.3789. Epub 2017 Feb 13.
• [5] CNOT2 Is Critically Involved in Atorvastatin Induced Apoptotic and Autophagic Cell Death in Non-Small Cell Lung Cancers.Cancers (Basel). 2019 Sep 30;11(10):1470. doi: 10.3390/cancers11101470.
• [6] Genome-wide association study (GWAS) of ovarian cancer in Japanese predicted regulatory variants in 22q13.1.PLoS One. 2018 Dec 17;13(12):e0209096. doi: 10.1371/journal.pone.0209096. eCollection 2018.
• [7] 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.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [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] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [11] 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.
• [12] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [13] 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.
• [14] 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.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [17] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [18] 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.
• [19] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [20] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.