Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGWJ4T4)

• DOT Name: RuvB-like 2 (RUVBL2)
• Synonyms: EC 3.6.4.12; 48 kDa TATA box-binding protein-interacting protein; 48 kDa TBP-interacting protein; 51 kDa erythrocyte cytosolic protein; ECP-51; INO80 complex subunit J; Repressing pontin 52; Reptin 52; TIP49b; TIP60-associated protein 54-beta; TAP54-beta
• Gene Name: RUVBL2
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Fanconi's anemia
  Hepatocellular carcinoma
  Immunodeficiency
  leukaemia
  Leukemia
  Neoplasm
  Prostate neoplasm
  Ebola virus infection
• UniProt ID: RUVB2_HUMAN
• PDB ID: 2CQA; 2XSZ; 3UK6; 5OAF; 6FO1; 6H7X; 6HTS; 6IGM; 6K0R; 6QI8; 6QI9; 7AHO; 7OLE; 7P6X; 7ZI4
• EC Number: 3.6.4.12
• Pfam ID: PF06068 ; PF17856
• Sequence:
  MATVTATTKVPEIRDVTRIERIGAHSHIRGLGLDDALEPRQASQGMVGQLAARRAAGVVL
  EMIREGKIAGRAVLIAGQPGTGKTAIAMGMAQALGPDTPFTAIAGSEIFSLEMSKTEALT
  QAFRRSIGVRIKEETEIIEGEVVEIQIDRPATGTGSKVGKLTLKTTEMETIYDLGTKMIE
  SLTKDKVQAGDVITIDKATGKISKLGRSFTRARDYDAMGSQTKFVQCPDGELQKRKEVVH
  TVSLHEIDVINSRTQGFLALFSGDTGEIKSEVREQINAKVAEWREEGKAEIIPGVLFIDE
  VHMLDIESFSFLNRALESDMAPVLIMATNRGITRIRGTSYQSPHGIPIDLLDRLLIVSTT
  PYSEKDTKQILRIRCEEEDVEMSEDAYTVLTRIGLETSLRYAIQLITAASLVCRKRKGTE
  VQVDDIKRVYSLFLDESRSTQYMKEYQDAFLFNELKGETMDTS
• Function: Possesses single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (5' to 3') 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. May also inhibit the transcriptional activity of ATF2. Involved in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway where it negatively regulates expression of ER stress response genes. May play a role in regulating the composition of the U5 snRNP complex.
• Tissue Specificity: Ubiquitously expressed. Highly expressed in testis and thymus.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway:
  HATs acetylate histones (R-HSA-3214847)
  Telomere Extension By Telomerase (R-HSA-171319)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[7]
leukaemia	DISS7D1V	Strong	Biomarker	[8]
Leukemia	DISNAKFL	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[9]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of RuvB-like 2 (RUVBL2).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of RuvB-like 2 (RUVBL2).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of RuvB-like 2 (RUVBL2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RuvB-like 2 (RUVBL2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RuvB-like 2 (RUVBL2).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of RuvB-like 2 (RUVBL2).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RuvB-like 2 (RUVBL2).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of RuvB-like 2 (RUVBL2).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RuvB-like 2 (RUVBL2).	[18]
Selenium	DM25CGV	Approved	Selenium increases the expression of RuvB-like 2 (RUVBL2).	[19]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of RuvB-like 2 (RUVBL2).	[20]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of RuvB-like 2 (RUVBL2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of RuvB-like 2 (RUVBL2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of RuvB-like 2 (RUVBL2).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of RuvB-like 2 (RUVBL2).	[26]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of RuvB-like 2 (RUVBL2).	[27]
Linalool	DMGZQ5P	Investigative	Linalool decreases the expression of RuvB-like 2 (RUVBL2).	[27]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin affects the binding of RuvB-like 2 (RUVBL2).	[16]

References

• [1] The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia.Leukemia. 2019 Dec;33(12):2817-2829. doi: 10.1038/s41375-019-0495-8. Epub 2019 May 28.
• [2] AAA+ ATPases Reptin and Pontin as potential diagnostic and prognostic biomarkers in salivary gland cancer - a short report.Cell Oncol (Dordr). 2018 Aug;41(4):455-462. doi: 10.1007/s13402-018-0382-8. Epub 2018 Jun 5.
• [3] Human TIP49b/RUVBL2 gene: genomic structure, expression pattern, physical link to the human CGB/LHB gene cluster on chromosome 19q13.3.Ann Genet. 2000 Apr-Jun;43(2):69-74. doi: 10.1016/s0003-3995(00)01016-9.
• [4] RuvBl2 cooperates with Ets2 to transcriptionally regulate hTERT in colon cancer.FEBS Lett. 2011 Aug 4;585(15):2537-44. doi: 10.1016/j.febslet.2011.07.005. Epub 2011 Jul 13.
• [5] 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.
• [6] Multilevel regulation of RUVBL2 expression predicts poor prognosis in hepatocellular carcinoma.Cancer Cell Int. 2019 Sep 27;19:249. doi: 10.1186/s12935-019-0974-z. eCollection 2019.
• [7] Overexpression and role of the ATPase and putative DNA helicase RuvB-like 2 in human hepatocellular carcinoma.Hepatology. 2007 Oct;46(4):1108-18. doi: 10.1002/hep.21770.
• [8] The AAA+ ATPase RUVBL2 is a critical mediator of MLL-AF9 oncogenesis.Leukemia. 2013 Jul;27(7):1461-8. doi: 10.1038/leu.2013.42. Epub 2013 Feb 13.
• [9] Subnuclear domain proteins in cancer cells support the functions of RUNX2 in the DNA damage response.J Cell Sci. 2015 Feb 15;128(4):728-40. doi: 10.1242/jcs.160051. Epub 2015 Jan 20.
• [10] 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.
• [11] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [12] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [13] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [14] Nuclear proteome analysis of cisplatin-treated HeLa cells. Mutat Res. 2010 Sep 10;691(1-2):1-8. doi: 10.1016/j.mrfmmm.2010.06.002. Epub 2010 Jun 9.
• [15] 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.
• [16] Biotinylated quercetin as an intrinsic photoaffinity proteomics probe for the identification of quercetin target proteins. Bioorg Med Chem. 2011 Aug 15;19(16):4710-20. doi: 10.1016/j.bmc.2011.07.005. Epub 2011 Jul 13.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [19] 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.
• [20] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [21] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [27] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.