Details of Drug Off-Target (DOT)

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

• DOT Name: Nuclear valosin-containing protein-like (NVL)
• Synonyms: NVLp; Nuclear VCP-like protein
• Gene Name: NVL
• Related Disease:
  Advanced cancer
  Diabetic retinopathy
  Major depressive disorder
  Schizophrenia
  Adrenoleukodystrophy
  Acute myelogenous leukaemia
• UniProt ID: NVL_HUMAN
• PDB ID: 2X8A; 6RO1
• Pfam ID: PF00004 ; PF17862 ; PF16725
• Sequence:
  MKPRPAGFVDNKLKQRVIQYLTSNKCGKYVDIGVLASDLQRVYSIDYGRRKRNAFRIQVE
  KVFSIISSEKELKNLTELEDEHLAKRARQGEEDNEYTESYSDDDSSMEDYPDPQSANHMN
  SSLLSLYRKGNPDSVSNTPEMEQRETTSSTPRISSKTGSIPLKTPAKDSEGGWFIDKTPS
  VKKDSFFLDLSCEKSNPKKPITEIQDSKDSSLLESDMKRKGKLKNKGSKRKKEDLQEVDG
  EIEAVLQKKAKARGLEFQISNVKFEDVGGNDMTLKEVCKMLIHMRHPEVYHHLGVVPPRG
  VLLHGPPGCGKTLLAHAIAGELDLPILKVAAPEIVSGVSGESEQKLRELFEQAVSNAPCI
  IFIDEIDAITPKREVASKDMERRIVAQLLTCMDDLNNVAATARVLVIGATNRPDSLDPAL
  RRAGRFDREICLGIPDEASRERILQTLCRKLRLPQAFDFCHLAHLTPGFVGADLMALCRE
  AAMCAVNRVLMKLQEQQKKNPEMEDLPSKGVQEERLGTEPTSETQDELQRLLGLLRDQDP
  LSEEQMQGLCIELNDFIVALSSVQPSAKREGFVTVPNVTWADIGALEDIREELTMAILAP
  VRNPDQFKALGLVTPAGVLLAGPPGCGKTLLAKAVANESGLNFISVKGPELLNMYVGESE
  RAVRQVFQRAKNSAPCVIFFDEVDALCPRRSDRETGASVRVVNQLLTEMDGLEARQQVFI
  MAATNRPDIIDPAILRPGRLDKTLFVGLPPPADRLAILKTITKNGTKPPLDADVNLEAIA
  GDLRCDCYTGADLSALVREASICALRQEMARQKSGNEKGELKVSHKHFEEAFKKVRSSIS
  KKDQIMYERLQESLSR
• Function: Participates in the assembly of the telomerase holoenzyme and effecting of telomerase activity via its interaction with TERT. Involved in both early and late stages of the pre-rRNA processing pathways. Spatiotemporally regulates 60S ribosomal subunit biogenesis in the nucleolus. Catalyzes the release of specific assembly factors, such as WDR74, from pre-60S ribosomal particles through the ATPase activity.
• Tissue Specificity: Widely expressed. Highest level of expression in heart, placenta, skeletal muscle, pancreas and retina.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[2]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[3]
Adrenoleukodystrophy	DISTUD1F	moderate	Genetic Variation	[4]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[5]

8 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 Nuclear valosin-containing protein-like (NVL).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nuclear valosin-containing protein-like (NVL).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nuclear valosin-containing protein-like (NVL).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Nuclear valosin-containing protein-like (NVL).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nuclear valosin-containing protein-like (NVL).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nuclear valosin-containing protein-like (NVL).	[13]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Nuclear valosin-containing protein-like (NVL).	[15]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Nuclear valosin-containing protein-like (NVL).	[16]

3 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 Nuclear valosin-containing protein-like (NVL).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Nuclear valosin-containing protein-like (NVL).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Nuclear valosin-containing protein-like (NVL).	[14]

References

• [1] Cryo-EM structure of the essential ribosome assembly AAA-ATPase Rix7.Nat Commun. 2019 Jan 31;10(1):513. doi: 10.1038/s41467-019-08373-0.
• [2] Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.Diabetes. 2019 Feb;68(2):441-456. doi: 10.2337/db18-0567. Epub 2018 Nov 28.
• [3] The NVL gene confers risk for both major depressive disorder and schizophrenia in the Han Chinese population.Prog Neuropsychopharmacol Biol Psychiatry. 2015 Oct 1;62:7-13. doi: 10.1016/j.pnpbp.2015.04.001. Epub 2015 Apr 17.
• [4] PNPLA3 Association with Alcoholic Liver Disease in a Cohort of Heavy Drinkers.Alcohol Alcohol. 2018 Jul 1;53(4):357-360. doi: 10.1093/alcalc/agy007.
• [5] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] 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.
• [8] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [9] 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.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [14] 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.
• [15] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [16] 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.