Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWA6RTX)

• DOT Name: NEDD8 ultimate buster 1 (NUB1)
• Synonyms: Negative regulator of ubiquitin-like proteins 1; Renal carcinoma antigen NY-REN-18
• Gene Name: NUB1
• Related Disease:
  Clear cell renal carcinoma
  Huntington disease
  Renal cell carcinoma
  Leber congenital amaurosis
  Leber congenital amaurosis 1
  Blindness
  Lewy body dementia
  Parkinson disease
• UniProt ID: NUB1_HUMAN
• PDB ID: 1WJU
• Pfam ID: PF00627 ; PF18037
• Sequence:
  MAQKKYLQAKLTQFLREDRIQLWKPPYTDENKKVGLALKDLAKQYSDRLECCENEVEKVI
  EEIRCKAIERGTGNDNYRTTGIATIEVFLPPRLKKDRKNLLETRLHITGRELRSKIAETF
  GLQENYIKIVINKKQLQLGKTLEEQGVAHNVKAMVLELKQSEEDARKNFQLEEEEQNEAK
  LKEKQIQRTKRGLEILAKRAAETVVDPEMTPYLDIANQTGRSIRIPPSERKALMLAMGYH
  EKGRAFLKRKEYGIALPCLLDADKYFCECCRELLDTVDNYAVLQLDIVWCYFRLEQLECL
  DDAEKKLNLAQKCFKNCYGENHQRLVHIKGNCGKEKVLFLRLYLLQGIRNYHSGNDVEAY
  EYLNKARQLFKELYIDPSKVDNLLQLGFTAQEARLGLRACDGNVDHAATHITNRREELAQ
  IRKEEKEKKRRRLENIRFLKGMGYSTHAAQQVLHAASGNLDEALKILLSNPQMWWLNDSN
  PETDNRQESPSQENIDRLVYMGFDALVAEAALRVFRGNVQLAAQTLAHNGGSLPPELPLS
  PEDSLSPPATSPSDSAGTSSASTDEDMETEAVNEILEDIPEHEEDYLDSTLEDEEIIIAE
  YLSYVENRKSATKKN
• Function: Specific down-regulator of the NEDD8 conjugation system. Recruits NEDD8, UBD, and their conjugates to the proteasome for degradation. Isoform 1 promotes the degradation of NEDD8 more efficiently than isoform 2.
• Tissue Specificity: Widely expressed with lowest expression in the pancreas for isoform 1 and in leukocytes, liver, prostate and skeletal muscle for isoform 2.
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[1]
Huntington disease	DISQPLA4	Strong	Biomarker	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[1]
Leber congenital amaurosis	DISMGH8F	moderate	Biomarker	[3]
Leber congenital amaurosis 1	DISY2B33	moderate	Biomarker	[3]
Blindness	DISTIM10	Limited	Biomarker	[3]
Lewy body dementia	DISAE66J	Limited	Posttranslational Modification	[4]
Parkinson disease	DISQVHKL	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NEDD8 ultimate buster 1 (NUB1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NEDD8 ultimate buster 1 (NUB1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NEDD8 ultimate buster 1 (NUB1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NEDD8 ultimate buster 1 (NUB1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of NEDD8 ultimate buster 1 (NUB1).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of NEDD8 ultimate buster 1 (NUB1).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of NEDD8 ultimate buster 1 (NUB1).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of NEDD8 ultimate buster 1 (NUB1).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of NEDD8 ultimate buster 1 (NUB1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of NEDD8 ultimate buster 1 (NUB1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of NEDD8 ultimate buster 1 (NUB1).	[16]

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 NEDD8 ultimate buster 1 (NUB1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of NEDD8 ultimate buster 1 (NUB1).	[14]

References

• [1] NUB1, an interferon-inducible protein, mediates anti-proliferative actions and apoptosis in renal cell carcinoma cells through cell-cycle regulation.Br J Cancer. 2010 Mar 2;102(5):873-82. doi: 10.1038/sj.bjc.6605574. Epub 2010 Feb 16.
• [2] Identification of NUB1 as a suppressor of mutant Huntington toxicity via enhanced protein clearance.Nat Neurosci. 2013 May;16(5):562-70. doi: 10.1038/nn.3367. Epub 2013 Mar 24.
• [3] Abolished interaction of NUB1 with mutant AIPL1 involved in Leber congenital amaurosis.Biochem Biophys Res Commun. 2004 May 7;317(3):768-73. doi: 10.1016/j.bbrc.2004.03.108.
• [4] Phosphorylated NUB1 distinguishes -synuclein in Lewy bodies from that in glial cytoplasmic inclusions in multiple system atrophy.Brain Pathol. 2019 Nov;29(6):803-812. doi: 10.1111/bpa.12728. Epub 2019 May 17.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [10] 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.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.