Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM8I5RH)

• DOT Name: CCR4-NOT transcription complex subunit 4 (CNOT4)
• Synonyms: EC 2.3.2.27; CCR4-associated factor 4; E3 ubiquitin-protein ligase CNOT4; Potential transcriptional repressor NOT4Hp; RING-type E3 ubiquitin transferase CNOT4
• Gene Name: CNOT4
• Related Disease:
  Hepatocellular carcinoma
  Influenza
  Neoplasm
  Peripheral arterial disease
• UniProt ID: CNOT4_HUMAN
• PDB ID: 1E4U; 1UR6
• EC Number: 2.3.2.27
• Pfam ID: PF00076 ; PF14570
• Sequence:
  MSRSPDAKEDPVECPLCMEPLEIDDINFFPCTCGYQICRFCWHRIRTDENGLCPACRKPY
  PEDPAVYKPLSQEELQRIKNEKKQKQNERKQKISENRKHLASVRVVQKNLVFVVGLSQRL
  ADPEVLKRPEYFGKFGKIHKVVINNSTSYAGSQGPSASAYVTYIRSEDALRAIQCVNNVV
  VDGRTLKASLGTTKYCSYFLKNMQCPKPDCMYLHELGDEAASFTKEEMQAGKHQEYEQKL
  LQELYKLNPNFLQLSTGSVDKNKNKVTPLQRYDTPIDKPSDSLSIGNGDNSQQISNSDTP
  SPPPGLSKSNPVIPISSSNHSARSPFEGAVTESQSLFSDNFRHPNPIPSGLPPFPSSPQT
  SSDWPTAPEPQSLFTSETIPVSSSTDWQAAFGFGSSKQPEDDLGFDPFDVTRKALADLIE
  KELSVQDQPSLSPTSLQNSSSHTTTAKGPGSGFLHPAAATNANSLNSTFSVLPQRFPQFQ
  QHRAVYNSFSFPGQAARYPWMAFPRNSIMHLNHTANPTSNSNFLDLNLPPQHNTGLGGIP
  VAGEEEVKVSTMPLSTSSHSLQQGQQPTSLHTTVA
• Function: Has E3 ubiquitin ligase activity, promoting ubiquitination and degradation of target proteins. Involved in activation of the JAK/STAT pathway. Catalyzes ubiquitination of methylated RBM15. Plays a role in quality control of translation of mitochondrial outer membrane-localized mRNA. As part of the PINK1-regulated signaling, upon mitochondria damage, ubiquitinates ABCE1 and thereby recruits autophagy receptors to the mitochondrial outer membrane to initiate mitophagy.
• 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[1]
Influenza	DIS3PNU3	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[4]

8 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 4 (CNOT4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CCR4-NOT transcription complex subunit 4 (CNOT4).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of CCR4-NOT transcription complex subunit 4 (CNOT4).	[7]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of CCR4-NOT transcription complex subunit 4 (CNOT4).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of CCR4-NOT transcription complex subunit 4 (CNOT4).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of CCR4-NOT transcription complex subunit 4 (CNOT4).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of CCR4-NOT transcription complex subunit 4 (CNOT4).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of CCR4-NOT transcription complex subunit 4 (CNOT4).	[12]

References

• [1] Hepatocellular carcinoma is associated with an increased risk of hepatitis B virus recurrence after liver transplantation.Gastroenterology. 2008 Jun;134(7):1890-9; quiz 2155. doi: 10.1053/j.gastro.2008.02.064. Epub 2008 Mar 4.
• [2] CNOT4-Mediated Ubiquitination of Influenza A Virus Nucleoprotein Promotes Viral RNA Replication.mBio. 2017 May 23;8(3):e00597-17. doi: 10.1128/mBio.00597-17.
• [3] Minimal residual disease after transplantation or lenalidomide-based consolidation in myeloma patients: a prospective analysis.Oncotarget. 2017 Jan 24;8(4):5924-5935. doi: 10.18632/oncotarget.12641.
• [4] Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.PLoS One. 2016 Apr 15;11(4):e0152670. doi: 10.1371/journal.pone.0152670. eCollection 2016.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [11] 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.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.