Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLBRR6Q)

• DOT Name: CCR4-NOT transcription complex subunit 6-like (CNOT6L)
• Synonyms: EC 3.1.13.4; Carbon catabolite repressor protein 4 homolog B
• Gene Name: CNOT6L
• Related Disease: B-cell lymphoma
• UniProt ID: CNO6L_HUMAN
• PDB ID: 3NGN; 3NGO; 3NGQ; 5DV2; 5DV4; 7VOI
• EC Number: 3.1.13.4
• Pfam ID: PF03372 ; PF13855
• Sequence:
  MRLIGMPKEKYDPPDPRRIYTIMSAEEVANGKKSHWAELEISGRVRSLSTSLWSLTHLTA
  LHLNDNYLSRIPPDIAKLHNLVYLDLSSNKLRSLPAELGNMVSLRELLLNNNLLRVLPYE
  LGRLFQLQTLGLKGNPLSQDILNLYQDPDGTRKLLNFMLDNLAVHPEQLPPRPWITLKER
  DQILPSASFTVMCYNVLCDKYATRQLYGYCPSWALNWEYRKKGIMEEIVNCDADIISLQE
  VETEQYFTLFLPALKERGYDGFFSPKSRAKIMSEQERKHVDGCAIFFKTEKFTLVQKHTV
  EFNQVAMANSDGSEAMLNRVMTKDNIGVAVVLEVHKELFGAGMKPIHAADKQLLIVANAH
  MHWDPEYSDVKLIQTMMFVSEVKNILEKASSRPGSPTADPNSIPLVLCADLNSLPDSGVV
  EYLSNGGVADNHKDFKELRYNECLMNFSCNGKNGSSEGRITHGFQLKSAYENNLMPYTNY
  TFDFKGVIDYIFYSKTHMNVLGVLGPLDPQWLVENNITGCPHPHIPSDHFSLLTQLELHP
  PLLPLVNGVHLPNRR
• Function: Has 3'-5' poly(A) exoribonuclease activity for synthetic poly(A) RNA substrate. Catalytic 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 the deadenylation-dependent degradation of mRNAs through the 3'-UTR AU-rich element-mediated mechanism. Involved in deadenylation-dependent degradation of CDKN1B mRNA. Its mRNA deadenylase activity can be inhibited by TOB1. Mediates cell proliferation and cell survival and prevents cellular senescence.
• Tissue Specificity: Highly expressed in placenta, skeletal muscle, pancreas, testis and leukocytes. Weakly expressed in heart, spleen and thymus.
• 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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[1]

12 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 6-like (CNOT6L).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CCR4-NOT transcription complex subunit 6-like (CNOT6L).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of CCR4-NOT transcription complex subunit 6-like (CNOT6L).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of CCR4-NOT transcription complex subunit 6-like (CNOT6L).	[5]
Marinol	DM70IK5	Approved	Marinol increases the expression of CCR4-NOT transcription complex subunit 6-like (CNOT6L).	[6]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of CCR4-NOT transcription complex subunit 6-like (CNOT6L).	[7]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of CCR4-NOT transcription complex subunit 6-like (CNOT6L).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of CCR4-NOT transcription complex subunit 6-like (CNOT6L).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of CCR4-NOT transcription complex subunit 6-like (CNOT6L).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of CCR4-NOT transcription complex subunit 6-like (CNOT6L).	[7]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of CCR4-NOT transcription complex subunit 6-like (CNOT6L).	[11]
Manganese	DMKT129	Investigative	Manganese increases the expression of CCR4-NOT transcription complex subunit 6-like (CNOT6L).	[12]

References

• [1] Identification of potential key genes associated with diffuse large B-cell lymphoma based on microarray gene expression profiling.Neoplasma. 2017;64(6):824-833. doi: 10.4149/neo_2017_603.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [6] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [7] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [8] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [9] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [10] 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.
• [11] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [12] 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.