Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4D5Z9L)

• DOT Name: CCR4-NOT transcription complex subunit 3 (CNOT3)
• Synonyms: CCR4-associated factor 3; Leukocyte receptor cluster member 2
• Gene Name: CNOT3
• Related Disease:
  Complex neurodevelopmental disorder
  Adult T-cell leukemia/lymphoma
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Colorectal carcinoma
  Congestive heart failure
  Intellectual developmental disorder with speech delay, autism, and dysmorphic facies
  Lipodystrophy
  Lung cancer
  Lung carcinoma
  Moyamoya disease
  Non-small-cell lung cancer
  Prostate cancer
  Prostate neoplasm
  Retinitis pigmentosa
  Adenovirus infection
  Advanced cancer
  Anemia
  Ankylosing spondylitis
  Hepatitis
  Hepatitis A virus infection
  Intellectual disability
  Neoplasm
  Neurodevelopmental disorder
• UniProt ID: CNOT3_HUMAN
• PDB ID: 4C0D; 4C0G; 5FU6; 5FU7
• Pfam ID: PF04153 ; PF04065
• Sequence:
  MADKRKLQGEIDRCLKKVSEGVEQFEDIWQKLHNAANANQKEKYEADLKKEIKKLQRLRD
  QIKTWVASNEIKDKRQLIDNRKLIETQMERFKVVERETKTKAYSKEGLGLAQKVDPAQKE
  KEEVGQWLTNTIDTLNMQVDQFESEVESLSVQTRKKKGDKDKQDRIEGLKRHIEKHRYHV
  RMLETILRMLDNDSILVDAIRKIKDDVEYYVDSSQDPDFEENEFLYDDLDLEDIPQALVA
  TSPPSHSHMEDEIFNQSSSTPTSTTSSSPIPPSPANCTTENSEDDKKRGRSTDSEVSQSP
  AKNGSKPVHSNQHPQSPAVPPTYPSGPPPAASALSTTPGNNGVPAPAAPPSALGPKASPA
  PSHNSGTPAPYAQAVAPPAPSGPSTTQPRPPSVQPSGGGGGGSGGGGSSSSSNSSAGGGA
  GKQNGATSYSSVVADSPAEVALSSSGGNNASSQALGPPSGPHNPPPSTSKEPSAAAPTGA
  GGVAPGSGNNSGGPSLLVPLPVNPPSSPTPSFSDAKAAGALLNGPPQFSTAPEIKAPEPL
  SSLKSMAERAAISSGIEDPVPTLHLTERDIILSSTSAPPASAQPPLQLSEVNIPLSLGVC
  PLGPVPLTKEQLYQQAMEEAAWHHMPHPSDSERIRQYLPRNPCPTPPYHHQMPPPHSDTV
  EFYQRLSTETLFFIFYYLEGTKAQYLAAKALKKQSWRFHTKYMMWFQRHEEPKTITDEFE
  QGTYIYFDYEKWGQRKKEGFTFEYRYLEDRDLQ
• 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. May be involved in metabolic regulation; may be involved in recruitment of the CCR4-NOT complex to deadenylation target mRNAs involved in energy metabolism. Involved in mitotic progression and regulation of the spindle assembly checkpoint by regulating the stability of MAD1L1 mRNA. Can repress transcription and may link the CCR4-NOT complex to transcriptional regulation; the repressive function may involve histone deacetylases. Involved in the maintenance of embryonic stem (ES) cell identity.
• Tissue Specificity: Ubiquitous. Highly expressed in brain, heart, thymus, spleen, kidney, liver, small intestine, 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

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Intellectual developmental disorder with speech delay, autism, and dysmorphic facies	DISOJZBL	Strong	Autosomal dominant	[6]
Lipodystrophy	DIS3SGVD	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Moyamoya disease	DISO62CA	Strong	Genetic Variation	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[11]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[12]
Adenovirus infection	DISUYSBZ	moderate	Altered Expression	[13]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[10]
Anemia	DISTVL0C	Limited	Biomarker	[14]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[15]
Hepatitis	DISXXX35	Limited	Biomarker	[14]
Hepatitis A virus infection	DISUMFQV	Limited	Biomarker	[14]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[16]
Neoplasm	DISZKGEW	Limited	Biomarker	[10]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	CCR4-NOT transcription complex subunit 3 (CNOT3) affects the response to substance of Methotrexate.	[25]

7 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 3 (CNOT3).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CCR4-NOT transcription complex subunit 3 (CNOT3).	[18]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of CCR4-NOT transcription complex subunit 3 (CNOT3).	[19]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of CCR4-NOT transcription complex subunit 3 (CNOT3).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of CCR4-NOT transcription complex subunit 3 (CNOT3).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of CCR4-NOT transcription complex subunit 3 (CNOT3).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of CCR4-NOT transcription complex subunit 3 (CNOT3).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of CCR4-NOT transcription complex subunit 3 (CNOT3).	[23]

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] Quantification of caveolin isoforms using quantitative real-time RT-PCR, and analysis of promoter CpG methylation of caveolin-1alpha in human T cell leukemia cell lines.Int J Mol Med. 2006 Sep;18(3):489-95.
• [3] Screening for Excessive Alcohol Use and Brief Counseling of Adults - 17 States and the District of Columbia, 2014.MMWR Morb Mortal Wkly Rep. 2017 Mar 31;66(12):313-319. doi: 10.15585/mmwr.mm6612a1.
• [4] The CCR4-NOT deadenylase complex controls Atg7-dependent cell death and heart function.Sci Signal. 2018 Feb 6;11(516):eaan3638. doi: 10.1126/scisignal.aan3638.
• [5] Transcriptional Regulator CNOT3 Defines an Aggressive Colorectal Cancer Subtype.Cancer Res. 2017 Feb 1;77(3):766-779. doi: 10.1158/0008-5472.CAN-16-1346. Epub 2016 Nov 29.
• [6] Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012 Apr 4;485(7397):246-50. doi: 10.1038/nature10989.
• [7] Adipocyte-specific disruption of mouse Cnot3 causes lipodystrophy.FEBS Lett. 2017 Jan;591(2):358-368. doi: 10.1002/1873-3468.12550. Epub 2017 Jan 12.
• [8] CNOT3 contributes to cisplatin resistance in lung cancer through inhibiting RIPK3 expression.Apoptosis. 2019 Aug;24(7-8):673-685. doi: 10.1007/s10495-019-01550-y.
• [9] The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.Genet Med. 2020 Feb;22(2):427-431. doi: 10.1038/s41436-019-0639-2. Epub 2019 Sep 2.
• [10] CNOT3 targets negative cell cycle regulators in non-small cell lung cancer development.Oncogene. 2019 Apr;38(14):2580-2594. doi: 10.1038/s41388-018-0603-7. Epub 2018 Dec 10.
• [11] Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.Nat Genet. 2018 May;50(5):682-692. doi: 10.1038/s41588-018-0086-z. Epub 2018 Apr 16.
• [12] Dominant PRPF31 mutations are hypostatic to a recessive CNOT3 polymorphism in retinitis pigmentosa: a novel phenomenon of "linked trans-acting epistasis".Ann Hum Genet. 2014 Jan;78(1):62-71. doi: 10.1111/ahg.12042. Epub 2013 Oct 14.
• [13] Degradation of a Novel DNA Damage Response Protein, Tankyrase 1 Binding Protein 1, following Adenovirus Infection.J Virol. 2018 May 29;92(12):e02034-17. doi: 10.1128/JVI.02034-17. Print 2018 Jun 15.
• [14] Insufficient liver maturation affects murine early postnatal hair cycle.Biochem Biophys Res Commun. 2020 Jan 1;521(1):172-177. doi: 10.1016/j.bbrc.2019.10.099. Epub 2019 Oct 18.
• [15] A high density SNP genotyping approach within the 19q13 chromosome region identifies an association of a CNOT3 polymorphism with ankylosing spondylitis.Ann Rheum Dis. 2012 May;71(5):714-7. doi: 10.1136/annrheumdis-2011-200661. Epub 2012 Jan 31.
• [16] De novo variants in CNOT3 cause a variable neurodevelopmental disorder.Eur J Hum Genet. 2019 Nov;27(11):1677-1682. doi: 10.1038/s41431-019-0413-6. Epub 2019 Jun 14.
• [17] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [18] 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.
• [19] 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.
• [20] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] 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.
• [24] 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.
• [25] 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.