Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLHKO3M)

• DOT Name: COP9 signalosome complex subunit 7a (COPS7A)
• Synonyms: SGN7a; Signalosome subunit 7a; Dermal papilla-derived protein 10; JAB1-containing signalosome subunit 7a
• Gene Name: COPS7A
• Related Disease:
  Stomach cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Gastric cancer
• UniProt ID: CSN7A_HUMAN
• PDB ID: 4D10; 4D18; 4WSN
• Pfam ID: PF18392 ; PF01399
• Sequence:
  MSAEVKVTGQNQEQFLLLAKSAKGAALATLIHQVLEAPGVYVFGELLDMPNVRELAESDF
  ASTFRLLTVFAYGTYADYLAEARNLPPLTEAQKNKLRHLSVVTLAAKVKCIPYAVLLEAL
  ALRNVRQLEDLVIEAVYADVLRGSLDQRNQRLEVDYSIGRDIQRQDLSAIARTLQEWCVG
  CEVVLSGIEEQVSRANQHKEQQLGLKQQIESEVANLKKTIKVTTAAAAAATSQDPEQHLT
  ELREPAPGTNQRQPSKKASKGKGLRGSAKIWSKSN
• Function: Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, JUN, I-kappa-B-alpha/NFKBIA, ITPK1 and IRF8/ICSBP, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively.
• Tissue Specificity: Widely expressed. Expressed at high level in brain, heart and skeletal muscle.
• Reactome Pathway:
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Neddylation (R-HSA-8951664)
  DNA Damage Recognition in GG-NER (R-HSA-5696394)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Stomach cancer	DISKIJSX	Definitive	Biomarker	[1]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[2]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of COP9 signalosome complex subunit 7a (COPS7A).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of COP9 signalosome complex subunit 7a (COPS7A).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of COP9 signalosome complex subunit 7a (COPS7A).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of COP9 signalosome complex subunit 7a (COPS7A).	[6]
Selenium	DM25CGV	Approved	Selenium increases the expression of COP9 signalosome complex subunit 7a (COPS7A).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of COP9 signalosome complex subunit 7a (COPS7A).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of COP9 signalosome complex subunit 7a (COPS7A).	[8]

References

• [1] Long non-coding RNA KRT19P3 suppresses proliferation and metastasis through COPS7A-mediated NF-B pathway in gastric cancer.Oncogene. 2019 Nov;38(45):7073-7088. doi: 10.1038/s41388-019-0934-z. Epub 2019 Aug 13.
• [2] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] 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.
• [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.