Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8ZPGWF)

• DOT Name: RNA-binding protein 15 (RBM15)
• Synonyms: One-twenty two protein 1; RNA-binding motif protein 15
• Gene Name: RBM15
• Related Disease:
  Acute leukaemia
  Acute megakaryoblastic leukemia
  Advanced cancer
  Childhood acute megakaryoblastic leukemia
  Laryngeal disorder
  leukaemia
  Leukemia
  Neoplasm
  Kaposi sarcoma
  Myeloid leukaemia
• UniProt ID: RBM15_HUMAN
• PDB ID: 7Z27
• Pfam ID: PF00076 ; PF07744
• Sequence:
  MRTAGRDPVPRRSPRWRRAVPLCETSAGRRVTQLRGDDLRRPATMKGKERSPVKAKRSRG
  GEDSTSRGERSKKLGGSGGSNGSSSGKTDSGGGSRRSLHLDKSSSRGGSREYDTGGGSSS
  SRLHSYSSPSTKNSSGGGESRSSSRGGGGESRSSGAASSAPGGGDGAEYKTLKISELGSQ
  LSDEAVEDGLFHEFKRFGDVSVKISHLSGSGSGDERVAFVNFRRPEDARAAKHARGRLVL
  YDRPLKIEAVYVSRRRSRSPLDKDTYPPSASVVGASVGGHRHPPGGGGGQRSLSPGGAAL
  GYRDYRLQQLALGRLPPPPPPPLPRDLERERDYPFYERVRPAYSLEPRVGAGAGAAPFRE
  VDEISPEDDQRANRTLFLGNLDITVTESDLRRAFDRFGVITEVDIKRPSRGQTSTYGFLK
  FENLDMSHRAKLAMSGKIIIRNPIKIGYGKATPTTRLWVGGLGPWVPLAALAREFDRFGT
  IRTIDYRKGDSWAYIQYESLDAAHAAWTHMRGFPLGGPDRRLRVDFADTEHRYQQQYLQP
  LPLTHYELVTDAFGHRAPDPLRGARDRTPPLLYRDRDRDLYPDSDWVPPPPPVRERSTRT
  AATSVPAYEPLDSLDRRRDGWSLDRDRGDRDLPSSRDQPRKRRLPEESGGRHLDRSPESD
  RPRKRHCAPSPDRSPELSSSRDRYNSDNDRSSRLLLERPSPIRDRRGSLEKSQGDKRDRK
  NSASAERDRKHRTTAPTEGKSPLKKEDRSDGSAPSTSTASSKLKSPSQKQDGGTAPVASA
  SPKLCLAWQGMLLLKNSNFPSNMHLLQGDLQVASSLLVEGSTGGKVAQLKITQRLRLDQP
  KLDEVTRRIKVAGPNGYAILLAVPGSSDSRSSSSSAASDTATSTQRPLRNLVSYLKQKQA
  AGVISLPVGGNKDKENTGVLHAFPPCEFSQQFLDSPAKALAKSEEDYLVMIIVRGFGFQI
  GVRYENKKRENLALTLL
• Function: RNA-binding protein that acts as a key regulator of N6-methyladenosine (m6A) methylation of RNAs, thereby regulating different processes, such as hematopoietic cell homeostasis, alternative splicing of mRNAs and X chromosome inactivation mediated by Xist RNA. Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing. Plays a key role in m6A methylation, possibly by binding target RNAs and recruiting the WMM complex. Involved in random X inactivation mediated by Xist RNA: acts by binding Xist RNA and recruiting the WMM complex, which mediates m6A methylation, leading to target YTHDC1 reader on Xist RNA and promoting transcription repression activity of Xist. Required for the development of multiple tissues, such as the maintenance of the homeostasis of long-term hematopoietic stem cells and for megakaryocyte (MK) and B-cell differentiation. Regulates megakaryocyte differentiation by regulating alternative splicing of genes important for megakaryocyte differentiation; probably regulates alternative splicing via m6A regulation. Required for placental vascular branching morphogenesis and embryonic development of the heart and spleen. Acts as a regulator of thrombopoietin response in hematopoietic stem cells by regulating alternative splicing of MPL. May also function as an mRNA export factor, stimulating export and expression of RTE-containing mRNAs which are present in many retrotransposons that require to be exported prior to splicing. High affinity binding of pre-mRNA to RBM15 may allow targeting of the mRNP to the export helicase DBP5 in a manner that is independent of splicing-mediated NXF1 deposition, resulting in export prior to splicing. May be implicated in HOX gene regulation.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[1]
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Childhood acute megakaryoblastic leukemia	DIS5VZDR	Strong	Biomarker	[4]
Laryngeal disorder	DISDKUQO	Strong	Biomarker	[5]
leukaemia	DISS7D1V	Strong	Biomarker	[6]
Leukemia	DISNAKFL	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Kaposi sarcoma	DISC1H1Z	Limited	Altered Expression	[8]
Myeloid leukaemia	DISMN944	Limited	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of RNA-binding protein 15 (RBM15).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RNA-binding protein 15 (RBM15).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of RNA-binding protein 15 (RBM15).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA-binding protein 15 (RBM15).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of RNA-binding protein 15 (RBM15).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of RNA-binding protein 15 (RBM15).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of RNA-binding protein 15 (RBM15).	[17]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of RNA-binding protein 15 (RBM15).	[18]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of RNA-binding protein 15 (RBM15).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RNA-binding protein 15 (RBM15).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of RNA-binding protein 15 (RBM15).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of RNA-binding protein 15 (RBM15).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of RNA-binding protein 15 (RBM15).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of RNA-binding protein 15 (RBM15).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of RNA-binding protein 15 (RBM15).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of RNA-binding protein 15 (RBM15).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of RNA-binding protein 15 (RBM15).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of RNA-binding protein 15 (RBM15).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of RNA-binding protein 15 (RBM15).	[15]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of RNA-binding protein 15 (RBM15).	[27]

References

• [1] Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia.Proc Natl Acad Sci U S A. 2001 May 8;98(10):5776-9. doi: 10.1073/pnas.101001498.
• [2] NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy.Genes Chromosomes Cancer. 2018 Jun;57(6):311-319. doi: 10.1002/gcc.22532. Epub 2018 Mar 28.
• [3] The molecular basis of leukemia.Hematology Am Soc Hematol Educ Program. 2004:80-97. doi: 10.1182/asheducation-2004.1.80.
• [4] New hPSC-based human models to study pediatric Acute Megakaryoblastic Leukemia harboring the fusion oncogene RBM15-MKL1.Stem Cell Res. 2017 Mar;19:1-5. doi: 10.1016/j.scr.2016.12.019. Epub 2016 Dec 19.
• [5] The Swallowing Characteristics of Thickeners, Jellies and Yoghurt Observed Using an In Vitro Model.Dysphagia. 2020 Aug;35(4):685-695. doi: 10.1007/s00455-019-10074-1. Epub 2019 Nov 9.
• [6] Fusion of OTT to BSAC results in aberrant up-regulation of transcriptional activity.J Biol Chem. 2008 Sep 26;283(39):26820-8. doi: 10.1074/jbc.M802315200. Epub 2008 Jul 30.
• [7] Pooled Analysis of external-beam RADiotherapy parameters in phase II and phase III trials in radiochemotherapy in Anal Cancer (PARADAC).Eur J Cancer. 2019 Nov;121:130-143. doi: 10.1016/j.ejca.2019.08.022. Epub 2019 Sep 28.
• [8] Multiple regions of Kaposi's sarcoma-associated herpesvirus ORF59 RNA are required for its expression mediated by viral ORF57 and cellular RBM15.Viruses. 2015 Feb 3;7(2):496-510. doi: 10.3390/v7020496.
• [9] Hemophagocytosis by leukemic megakaryoblasts in acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13;q13);RBM15-MKL1.J Pediatr Hematol Oncol. 2012 Oct;34(7):576-80. doi: 10.1097/MPH.0b013e318245a027.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] 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.
• [14] Role of N6-methyladenosine RNA modification in the imbalanced inflammatory homeostasis of arsenic-induced skin lesions. Environ Toxicol. 2022 Aug;37(8):1831-1839. doi: 10.1002/tox.23530. Epub 2022 Apr 1.
• [15] 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.
• [16] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [19] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [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] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [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] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.