Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTEU05F)

• DOT Name: CCR4-NOT transcription complex subunit 1 (CNOT1)
• Synonyms: CCR4-associated factor 1; Negative regulator of transcription subunit 1 homolog; NOT1H; hNOT1
• Gene Name: CNOT1
• Related Disease:
  Complex neurodevelopmental disorder
  Advanced cancer
  Bone osteosarcoma
  Cardiovascular disease
  Delirium
  Glioblastoma multiforme
  Hepatitis C virus infection
  Holoprosencephaly 12 with or without pancreatic agenesis
  Osteosarcoma
  Schizophrenia
  Vibrio cholerae infection
  Vissers-Bodmer syndrome
  Small lymphocytic lymphoma
  Neuroblastoma
• UniProt ID: CNOT1_HUMAN
• PDB ID: 4C0D; 4CQO; 4CRU; 4CRV; 4CRW; 4CT4; 4CT6; 4CT7; 4GMJ; 4GML; 4J8S; 5ANR; 5FU6; 5FU7; 5ONA; 7VOI; 8BFI; 8FY3
• Pfam ID: PF16415 ; PF16418 ; PF16417 ; PF12842 ; PF04054
• Sequence:
  MNLDSLSLALSQISYLVDNLTKKNYRASQQEIQHIVNRHGPEADRHLLRCLFSHVDFSGD
  GKSSGKDFHQTQFLIQECALLITKPNFISTLSYAIDNPLHYQKSLKPAPHLFAQLSKVLK
  LSKVQEVIFGLALLNSSSSDLRGFAAQFIKQKLPDLLRSYIDADVSGNQEGGFQDIAIEV
  LHLLLSHLLFGQKGAFGVGQEQIDAFLKTLRRDFPQERCPVVLAPLLYPEKRDILMDRIL
  PDSGGVAKTMMESSLADFMQEVGYGFCASIEECRNIIVQFGVREVTAAQVARVLGMMART
  HSGLTDGIPLQSISAPGSGIWSDGKDKSDGAQAHTWNVEVLIDVLKELNPSLNFKEVTYE
  LDHPGFQIRDSKGLHNVVYGIQRGLGMEVFPVDLIYRPWKHAEGQLSFIQHSLINPEIFC
  FADYPCHTVATDILKAPPEDDNREIATWKSLDLIESLLRLAEVGQYEQVKQLFSFPIKHC
  PDMLVLALLQINTSWHTLRHELISTLMPIFLGNHPNSAIILHYAWHGQGQSPSIRQLIMH
  AMAEWYMRGEQYDQAKLSRILDVAQDLKALSMLLNGTPFAFVIDLAALASRREYLKLDKW
  LTDKIREHGEPFIQACMTFLKRRCPSILGGLAPEKDQPKSAQLPPETLATMLACLQACAG
  SVSQELSETILTMVANCSNVMNKARQPPPGVMPKGRPPSASSLDAISPVQIDPLAGMTSL
  SIGGSAAPHTQSMQGFPPNLGSAFSTPQSPAKAFPPLSTPNQTTAFSGIGGLSSQLPVGG
  LGTGSLTGIGTGALGLPAVNNDPFVQRKLGTSGLNQPTFQQSKMKPSDLSQVWPEANQHF
  SKEIDDEANSYFQRIYNHPPHPTMSVDEVLEMLQRFKDSTIKREREVFNCMLRNLFEEYR
  FFPQYPDKELHITACLFGGIIEKGLVTYMALGLALRYVLEALRKPFGSKMYYFGIAALDR
  FKNRLKDYPQYCQHLASISHFMQFPHHLQEYIEYGQQSRDPPVKMQGSITTPGSIALAQA
  QAQAQVPAKAPLAGQVSTMVTTSTTTTVAKTVTVTRPTGVSFKKDVPPSINTTNIDTLLV
  ATDQTERIVEPPENIQEKIAFIFNNLSQSNMTQKVEELKETVKEEFMPWVSQYLVMKRVS
  IEPNFHSLYSNFLDTLKNPEFNKMVLNETYRNIKVLLTSDKAAANFSDRSLLKNLGHWLG
  MITLAKNKPILHTDLDVKSLLLEAYVKGQQELLYVVPFVAKVLESSIRSVVFRPPNPWTM
  AIMNVLAELHQEHDLKLNLKFEIEVLCKNLALDINELKPGNLLKDKDRLKNLDEQLSAPK
  KDVKQPEELPPITTTTTSTTPATNTTCTATVPPQPQYSYHDINVYSLAGLAPHITLNPTI
  PLFQAHPQLKQCVRQAIERAVQELVHPVVDRSIKIAMTTCEQIVRKDFALDSEESRMRIA
  AHHMMRNLTAGMAMITCREPLLMSISTNLKNSFASALRTASPQQREMMDQAAAQLAQDNC
  ELACCFIQKTAVEKAGPEMDKRLATEFELRKHARQEGRRYCDPVVLTYQAERMPEQIRLK
  VGGVDPKQLAVYEEFARNVPGFLPTNDLSQPTGFLAQPMKQAWATDDVAQIYDKCITELE
  QHLHAIPPTLAMNPQAQALRSLLEVVVLSRNSRDAIAALGLLQKAVEGLLDATSGADADL
  LLRYRECHLLVLKALQDGRAYGSPWCNKQITRCLIECRDEYKYNVEAVELLIRNHLVNMQ
  QYDLHLAQSMENGLNYMAVAFAMQLVKILLVDERSVAHVTEADLFHTIETLMRINAHSRG
  NAPEGLPQLMEVVRSNYEAMIDRAHGGPNFMMHSGISQASEYDDPPGLREKAEYLLREWV
  NLYHSAAAGRDSTKAFSAFVGQMHQQGILKTDDLITRFFRLCTEMCVEISYRAQAEQQHN
  PAANPTMIRAKCYHNLDAFVRLIALLVKHSGEATNTVTKINLLNKVLGIVVGVLLQDHDV
  RQSEFQQLPYHRIFIMLLLELNAPEHVLETINFQTLTAFCNTFHILRPTKAPGFVYAWLE
  LISHRIFIARMLAHTPQQKGWPMYAQLLIDLFKYLAPFLRNVELTKPMQILYKGTLRVLL
  VLLHDFPEFLCDYHYGFCDVIPPNCIQLRNLILSAFPRNMRLPDPFTPNLKVDMLSEINI
  APRILTNFTGVMPPQFKKDLDSYLKTRSPVTFLSDLRSNLQVSNEPGNRYNLQLINALVL
  YVGTQAIAHIHNKGSTPSMSTITHSAHMDIFQNLAVDLDTEGRYLFLNAIANQLRYPNSH
  THYFSCTMLYLFAEANTEAIQEQITRVLLERLIVNRPHPWGLLITFIELIKNPAFKFWNH
  EFVHCAPEIEKLFQSVAQCCMGQKQAQQVMEGTGAS
• Function: Scaffolding 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. Its scaffolding function implies its interaction with the catalytic complex module and diverse RNA-binding proteins mediating the complex recruitment to selected mRNA 3'UTRs. Involved in degradation of AU-rich element (ARE)-containing mRNAs probably via association with ZFP36. Mediates the recruitment of the CCR4-NOT complex to miRNA targets and to the RISC complex via association with TNRC6A, TNRC6B or TNRC6C. Acts as a transcriptional repressor. Represses the ligand-dependent transcriptional activation by nuclear receptors. Involved in the maintenance of embryonic stem (ES) cell identity.
• Tissue Specificity: Strongly expressed in brain, heart, thymus, spleen, kidney, liver, placenta and lung. Weakly expressed in skeletal muscle and colon.
• 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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[3]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[4]
Delirium	DIS2OKP1	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Posttranslational Modification	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Holoprosencephaly 12 with or without pancreatic agenesis	DISN7ZB3	Strong	Autosomal dominant	[8]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[9]
Vibrio cholerae infection	DISW7E3U	Strong	Biomarker	[10]
Vissers-Bodmer syndrome	DISD7U9U	Strong	Autosomal dominant	[11]
Small lymphocytic lymphoma	DIS30POX	moderate	Genetic Variation	[12]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of CCR4-NOT transcription complex subunit 1 (CNOT1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CCR4-NOT transcription complex subunit 1 (CNOT1).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of CCR4-NOT transcription complex subunit 1 (CNOT1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CCR4-NOT transcription complex subunit 1 (CNOT1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of CCR4-NOT transcription complex subunit 1 (CNOT1).	[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 CCR4-NOT transcription complex subunit 1 (CNOT1).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of CCR4-NOT transcription complex subunit 1 (CNOT1).	[20]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of CCR4-NOT transcription complex subunit 1 (CNOT1).	[19]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Molecular partners of hNOT/ALG3, the human counterpart of the Drosophila NOT and yeast ALG3 gene, suggest its involvement in distinct cellular processes relevant to congenital disorders of glycosylation, cancer, neurodegeneration and a variety of further pathologies.Hum Mol Genet. 2018 Jun 1;27(11):1858-1878. doi: 10.1093/hmg/ddy087.
• [3] CNOT1 cooperates with LMNA to aggravate osteosarcoma tumorigenesis through the Hedgehog signaling pathway.Mol Oncol. 2017 Apr;11(4):388-404. doi: 10.1002/1878-0261.12043. Epub 2017 Mar 6.
• [4] Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study.Lancet HIV. 2018 Jun;5(6):e291-e300. doi: 10.1016/S2352-3018(18)30043-2. Epub 2018 May 3.
• [5] Clinical phenotypes of delirium during critical illness and severity of subsequent long-term cognitive impairment: a prospective cohort study.Lancet Respir Med. 2018 Mar;6(3):213-222. doi: 10.1016/S2213-2600(18)30062-6.
• [6] Molecular mechanisms of regulation and action of microRNA-199a in testicular germ cell tumor and glioblastomas.PLoS One. 2013 Dec 31;8(12):e83980. doi: 10.1371/journal.pone.0083980. eCollection 2013.
• [7] Eukaryotic translation initiation factor 4AII contributes to microRNA-122 regulation of hepatitis C virus replication.Nucleic Acids Res. 2018 Jul 6;46(12):6330-6343. doi: 10.1093/nar/gky262.
• [8] A CCR4-NOT Transcription Complex, Subunit 1, CNOT1, Variant Associated with Holoprosencephaly. Am J Hum Genet. 2019 May 2;104(5):990-993. doi: 10.1016/j.ajhg.2019.03.017. Epub 2019 Apr 18.
• [9] Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
• [10] Retrospective genomic analysis of Vibrio cholerae O1 El Tor strains from different places in India reveals the presence of ctxB-7 allele found in Haitian isolates.Epidemiol Infect. 2017 Aug;145(11):2212-2220. doi: 10.1017/S0950268817001182.
• [11] De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay. Am J Hum Genet. 2020 Jul 2;107(1):164-172. doi: 10.1016/j.ajhg.2020.05.017. Epub 2020 Jun 17.
• [12] Genetic variants in miRNA processing genes and pre-miRNAs are associated with the risk of chronic lymphocytic leukemia.PLoS One. 2015 Mar 20;10(3):e0118905. doi: 10.1371/journal.pone.0118905. eCollection 2015.
• [13] Deregulation of focal adhesion pathway mediated by miR-659-3p is implicated in bone marrow infiltration of stage M neuroblastoma patients.Oncotarget. 2015 May 30;6(15):13295-308. doi: 10.18632/oncotarget.3745.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] 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.
• [16] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [17] 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.
• [18] 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.
• [19] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [20] 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.
• [21] 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.