Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWV19L7)

• DOT Name: RuvB-like 1 (RUVBL1)
• Synonyms: EC 3.6.4.12; 49 kDa TATA box-binding protein-interacting protein; 49 kDa TBP-interacting protein; 54 kDa erythrocyte cytosolic protein; ECP-54; INO80 complex subunit H; Nuclear matrix protein 238; NMP 238; Pontin 52; TIP49a; TIP60-associated protein 54-alpha; TAP54-alpha
• Gene Name: RUVBL1
• Related Disease:
  Bone osteosarcoma
  Osteosarcoma
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cardiovascular disease
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Epithelial ovarian cancer
  Familial adenomatous polyposis
  Fanconi's anemia
  Hepatocellular carcinoma
  Hydrocephalus
  Invasive breast carcinoma
  Kidney failure
  Liver cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Nephropathy
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Prostate neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
  Cervical cancer
  Cervical carcinoma
  Ebola virus infection
• UniProt ID: RUVB1_HUMAN
• PDB ID: 2C9O; 2XSZ; 5OAF; 6FO1; 6HTS; 6IGM; 6K0R; 6QI8; 6QI9; 7AHO; 7OLE; 7P6X; 7ZI4
• EC Number: 3.6.4.12
• Pfam ID: PF06068 ; PF17856
• Sequence:
  MKIEEVKSTTKTQRIASHSHVKGLGLDESGLAKQAASGLVGQENAREACGVIVELIKSKK
  MAGRAVLLAGPPGTGKTALALAIAQELGSKVPFCPMVGSEVYSTEIKKTEVLMENFRRAI
  GLRIKETKEVYEGEVTELTPCETENPMGGYGKTISHVIIGLKTAKGTKQLKLDPSIFESL
  QKERVEAGDVIYIEANSGAVKRQGRCDTYATEFDLEAEEYVPLPKGDVHKKKEIIQDVTL
  HDLDVANARPQGGQDILSMMGQLMKPKKTEITDKLRGEINKVVNKYIDQGIAELVPGVLF
  VDEVHMLDIECFTYLHRALESSIAPIVIFASNRGNCVIRGTEDITSPHGIPLDLLDRVMI
  IRTMLYTPQEMKQIIKIRAQTEGINISEEALNHLGEIGTKTTLRYSVQLLTPANLLAKIN
  GKDSIEKEHVEEISELFYDAKSSAKILADQQDKYMK
• Function: Possesses single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (3' to 5') activity; hexamerization is thought to be critical for ATP hydrolysis and adjacent subunits in the ring-like structure contribute to the ATPase activity. Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome-DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome. Proposed core component of the chromatin remodeling INO80 complex which exhibits DNA- and nucleosome-activated ATPase activity and catalyzes ATP-dependent nucleosome sliding. Plays an essential role in oncogenic transformation by MYC and also modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex. Essential for cell proliferation. May be able to bind plasminogen at cell surface and enhance plasminogen activation.
• Tissue Specificity: Ubiquitously expressed with high expression in heart, skeletal muscle and testis.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Wnt sig.ling pathway (hsa04310)
• Reactome Pathway:
  Formation of the beta-catenin (R-HSA-201722)
  HATs acetylate histones (R-HSA-3214847)
  UCH proteinases (R-HSA-5689603)
  Ub-specific processing proteases (R-HSA-5689880)
  DNA Damage Recognition in GG-NER (R-HSA-5696394)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  Telomere Extension By Telomerase (R-HSA-171319)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Altered Expression	[1]
Osteosarcoma	DISLQ7E2	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Familial adenomatous polyposis	DISW53RE	Strong	Altered Expression	[8]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[10]
Invasive breast carcinoma	DISANYTW	Strong	Biomarker	[4]
Kidney failure	DISOVQ9P	Strong	Biomarker	[10]
Liver cancer	DISDE4BI	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[11]
Lung cancer	DISCM4YA	Strong	Biomarker	[11]
Lung carcinoma	DISTR26C	Strong	Biomarker	[11]
Nephropathy	DISXWP4P	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[12]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[12]
Pancreatic cancer	DISJC981	Strong	Biomarker	[13]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[14]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Disputed	Altered Expression	[15]
Cervical carcinoma	DIST4S00	Disputed	Altered Expression	[15]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[16]

18 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 RuvB-like 1 (RUVBL1).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of RuvB-like 1 (RUVBL1).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RuvB-like 1 (RUVBL1).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of RuvB-like 1 (RUVBL1).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of RuvB-like 1 (RUVBL1).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of RuvB-like 1 (RUVBL1).	[22]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of RuvB-like 1 (RUVBL1).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RuvB-like 1 (RUVBL1).	[24]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of RuvB-like 1 (RUVBL1).	[25]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of RuvB-like 1 (RUVBL1).	[26]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of RuvB-like 1 (RUVBL1).	[27]
Selenium	DM25CGV	Approved	Selenium increases the expression of RuvB-like 1 (RUVBL1).	[28]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of RuvB-like 1 (RUVBL1).	[29]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of RuvB-like 1 (RUVBL1).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of RuvB-like 1 (RUVBL1).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of RuvB-like 1 (RUVBL1).	[33]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of RuvB-like 1 (RUVBL1).	[34]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of RuvB-like 1 (RUVBL1).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of RuvB-like 1 (RUVBL1).	[32]

References

• [1] CircMYO10 promotes osteosarcoma progression by regulating miR-370-3p/RUVBL1 axis to enhance the transcriptional activity of -catenin/LEF1 complex via effects on chromatin remodeling.Mol Cancer. 2019 Oct 29;18(1):150. doi: 10.1186/s12943-019-1076-1.
• [2] Functional genetic variants of RUVBL1 predict overall survival of Chinese patients with epithelial ovarian cancer.Carcinogenesis. 2019 Oct 16;40(10):1209-1219. doi: 10.1093/carcin/bgz092.
• [3] Gene Expression Profile of the Clinically Aggressive Micropapillary Variant of Bladder Cancer.Eur Urol. 2016 Oct;70(4):611-620. doi: 10.1016/j.eururo.2016.02.056. Epub 2016 Mar 15.
• [4] RUVBL1-ITFG1 interaction is required for collective invasion in breast cancer.Biochim Biophys Acta Gen Subj. 2017 Jul;1861(7):1788-1800. doi: 10.1016/j.bbagen.2017.03.016. Epub 2017 Mar 21.
• [5] Liver haploinsufficiency of RuvBL1 causes hepatic insulin resistance and enhances hepatocellular carcinoma progression.Int J Cancer. 2020 Jun 15;146(12):3410-3422. doi: 10.1002/ijc.32787. Epub 2019 Nov 28.
• [6] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [7] Regulation of COX-2 transcription in a colon cancer cell line by Pontin52/TIP49a.Mol Cancer. 2003 Dec 15;2:42. doi: 10.1186/1476-4598-2-42.
• [8] Proteins of the Wnt signaling pathway as targets for the regulation of CD133+ cancer stem cells in glioblastoma.Oncol Rep. 2019 May;41(5):3080-3088. doi: 10.3892/or.2019.7043. Epub 2019 Mar 5.
• [9] Abundance of the Fanconi anaemia core complex is regulated by the RuvBL1 and RuvBL2 AAA+ ATPases.Nucleic Acids Res. 2014 Dec 16;42(22):13736-48. doi: 10.1093/nar/gku1230. Epub 2014 Nov 26.
• [10] Targeted deletion of the AAA-ATPase Ruvbl1 in mice disrupts ciliary integrity and causes renal disease and hydrocephalus.Exp Mol Med. 2018 Jun 28;50(6):1-17. doi: 10.1038/s12276-018-0108-z.
• [11] RUVBL1, a novel C-RAF-binding protein, activates the RAF/MEK/ERK pathway to promote lung cancer tumorigenesis.Biochem Biophys Res Commun. 2018 Apr 15;498(4):932-939. doi: 10.1016/j.bbrc.2018.03.084. Epub 2018 Mar 15.
• [12] Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer.Int J Cancer. 2011 May 1;128(9):2063-74. doi: 10.1002/ijc.25554.
• [13] RUVBL1 directly binds actin filaments and induces formation of cell protrusions to promote pancreatic cancer cell invasion.Int J Oncol. 2014 Jun;44(6):1945-54. doi: 10.3892/ijo.2014.2380. Epub 2014 Apr 10.
• [14] SUMOylation of pontin chromatin-remodeling complex reveals a signal integration code in prostate cancer cells.Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20793-8. doi: 10.1073/pnas.0710343105. Epub 2007 Dec 17.
• [15] Profiling protein markers associated with the sensitivity to concurrent chemoradiotherapy in human cervical carcinoma.J Proteome Res. 2009 Aug;8(8):3969-76. doi: 10.1021/pr900287a.
• [16] Identification of RUVBL1 and RUVBL2 as Novel Cellular Interactors of the Ebola Virus Nucleoprotein.Viruses. 2019 Apr 23;11(4):372. doi: 10.3390/v11040372.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [20] 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.
• [21] 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.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [24] 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.
• [25] Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
• [26] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [27] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [28] 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.
• [29] Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis. Mol Biosyst. 2014 Jun;10(6):1332-44.
• [30] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [31] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [32] 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.
• [33] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [34] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [35] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.