Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5SR6G0)

• DOT Name: RNA-binding protein 8A (RBM8A)
• Synonyms: Binder of OVCA1-1; BOV-1; RNA-binding motif protein 8A; RNA-binding protein Y14; Ribonucleoprotein RBM8A
• Gene Name: RBM8A
• Related Disease:
  Neoplasm
  Thrombocytopenia-absent radius syndrome
  Advanced cancer
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Aortic aneurysm
  Chronic obstructive pulmonary disease
  Dementia
  High blood pressure
  HIV infectious disease
  Hyperlipidemia
  Immunodeficiency
  Isolated congenital microcephaly
  Non-small-cell lung cancer
  Hepatocellular carcinoma
  Pneumonia
  Anxiety
  Anxiety disorder
  Autism
  Dyskeratosis congenita, autosomal recessive 5
  Intellectual disability
  Marfan syndrome
  Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3
  Stroke
  Thrombocytopenia
• UniProt ID: RBM8A_HUMAN
• PDB ID: 1P27; 2HYI; 2J0Q; 2J0S; 2XB2; 3EX7; 5XJC; 5YZG; 6ICZ; 6QDV; 7A5P; 7W59; 7W5A; 7W5B; 7ZNJ; 8C6J
• Pfam ID: PF00076
• Sequence:
  MADVLDLHEAGGEDFAMDEDGDESIHKLKEKAKKRKGRGFGSEEGSRARMREDYDSVEQD
  GDEPGPQRSVEGWILFVTGVHEEATEEDIHDKFAEYGEIKNIHLNLDRRTGYLKGYTLVE
  YETYKEAQAAMEGLNGQDLMGQPISVDWCFVRGPPKGKRRGGRRRSRSPDRRRR
• Function: Required for pre-mRNA splicing as component of the spliceosome. Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). The MAGOH-RBM8A heterodimer inhibits the ATPase activity of EIF4A3, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The MAGOH-RBM8A heterodimer interacts with the EJC key regulator PYM1 leading to EJC disassembly in the cytoplasm and translation enhancement of EJC-bearing spliced mRNAs by recruiting them to the ribosomal 48S preinitiation complex. Its removal from cytoplasmic mRNAs requires translation initiation from EJC-bearing spliced mRNAs. Associates preferentially with mRNAs produced by splicing. Does not interact with pre-mRNAs, introns, or mRNAs produced from intronless cDNAs. Associates with both nuclear mRNAs and newly exported cytoplasmic mRNAs. The MAGOH-RBM8A heterodimer is a component of the nonsense mediated decay (NMD) pathway. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  mR. surveillance pathway (hsa03015)
  Spliceosome (hsa03040)
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA 3'-end processing (R-HSA-72187)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Thrombocytopenia-absent radius syndrome	DIS5CVW9	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[5]
Aortic aneurysm	DISQ5KRA	Strong	Genetic Variation	[6]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[3]
Dementia	DISXL1WY	Strong	Genetic Variation	[7]
High blood pressure	DISY2OHH	Strong	Biomarker	[8]
HIV infectious disease	DISO97HC	Strong	Biomarker	[9]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[8]
Immunodeficiency	DIS093I0	Strong	Biomarker	[10]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[12]
Pneumonia	DIS8EF3M	Disputed	Biomarker	[13]
Anxiety	DISIJDBA	Limited	Biomarker	[14]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[14]
Autism	DISV4V1Z	Limited	Genetic Variation	[14]
Dyskeratosis congenita, autosomal recessive 5	DIS7H2M2	Limited	Biomarker	[15]
Intellectual disability	DISMBNXP	Limited	Biomarker	[16]
Marfan syndrome	DISVEUWZ	Limited	Biomarker	[17]
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3	DISK1NTB	Limited	Biomarker	[15]
Stroke	DISX6UHX	Limited	Genetic Variation	[6]
Thrombocytopenia	DISU61YW	Limited	Genetic Variation	[18]

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 8A (RBM8A).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of RNA-binding protein 8A (RBM8A).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of RNA-binding protein 8A (RBM8A).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of RNA-binding protein 8A (RBM8A).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA-binding protein 8A (RBM8A).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RNA-binding protein 8A (RBM8A).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of RNA-binding protein 8A (RBM8A).	[25]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of RNA-binding protein 8A (RBM8A).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of RNA-binding protein 8A (RBM8A).	[27]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of RNA-binding protein 8A (RBM8A).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of RNA-binding protein 8A (RBM8A).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of RNA-binding protein 8A (RBM8A).	[32]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of RNA-binding protein 8A (RBM8A).	[33]
PP-242	DM2348V	Investigative	PP-242 increases the expression of RNA-binding protein 8A (RBM8A).	[34]

3 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 RNA-binding protein 8A (RBM8A).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of RNA-binding protein 8A (RBM8A).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of RNA-binding protein 8A (RBM8A).	[30]

References

• [1] A Y(1) receptor ligand synergized with a P-glycoprotein inhibitor improves the therapeutic efficacy of multidrug resistant breast cancer.Biomater Sci. 2019 Nov 1;7(11):4748-4757. doi: 10.1039/c9bm00337a. Epub 2019 Sep 11.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Total arch replacement versus debranching thoracic endovascular aortic repair for aortic arch aneurysm: what indicates a high-risk patient for arch repair in octogenarians?.Gen Thorac Cardiovasc Surg. 2018 May;66(5):263-269. doi: 10.1007/s11748-018-0894-1. Epub 2018 Jan 31.
• [4] Identification of molecular correlations of RBM8A with autophagy in Alzheimer's disease.Aging (Albany NY). 2019 Dec 9;11(23):11673-11685. doi: 10.18632/aging.102571. Epub 2019 Dec 9.
• [5] Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization.Mol Ther. 2017 Jan 4;25(1):127-139. doi: 10.1016/j.ymthe.2016.10.013. Epub 2017 Jan 4.
• [6] Clinical outcomes of different surgical approaches for proximal descending thoracic aneurysm involving the distal arch.J Thorac Cardiovasc Surg. 2018 Jun;155(6):2289-2298.e1. doi: 10.1016/j.jtcvs.2017.12.152. Epub 2018 Feb 20.
• [7] Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD.J Exp Med. 2014 Sep 22;211(10):1937-45. doi: 10.1084/jem.20140214. Epub 2014 Aug 25.
• [8] Efficacy and Tolerability of Telmisartan/Amlodipine and Rosuvastatin Coadministration in Hypertensive Patients with Hyperlipidemia: A Phase III, Multicenter, Randomized, Double-blind Study.Clin Ther. 2019 Apr;41(4):728-741. doi: 10.1016/j.clinthera.2019.02.013. Epub 2019 Mar 21.
• [9] RNAi in combination with a ribozyme and TAR decoy for treatment of HIV infection in hematopoietic cell gene therapy.Ann N Y Acad Sci. 2006 Oct;1082:172-9. doi: 10.1196/annals.1348.006.
• [10] shRNAmediated silencing of TARBP2 inhibits NCIH1299 nonsmall cell lung cancer cell invasion and migration via the JNK/STAT3/AKT pathway.Mol Med Rep. 2016 Oct;14(4):3725-30. doi: 10.3892/mmr.2016.5723. Epub 2016 Sep 6.
• [11] Rbm8a haploinsufficiency disrupts embryonic cortical development resulting in microcephaly.J Neurosci. 2015 May 6;35(18):7003-18. doi: 10.1523/JNEUROSCI.0018-15.2015.
• [12] Expression and gene regulation network of RBM8A in hepatocellular carcinoma based on data mining.Aging (Albany NY). 2019 Jan 22;11(2):423-447. doi: 10.18632/aging.101749.
• [13] Virome and bacteriome characterization of children with pneumonia and asthma in Mexico City during winter seasons 2014 and 2015.PLoS One. 2018 Feb 15;13(2):e0192878. doi: 10.1371/journal.pone.0192878. eCollection 2018.
• [14] An EJC factor RBM8a regulates anxiety behaviors.Curr Mol Med. 2013 Jul;13(6):887-99. doi: 10.2174/15665240113139990019.
• [15] Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet. 2007 Feb;80(2):232-40. doi: 10.1086/510919. Epub 2006 Dec 21.
• [16] Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders.Hum Mol Genet. 2013 May 1;22(9):1816-25. doi: 10.1093/hmg/ddt035. Epub 2013 Jan 31.
• [17] Total arch replacement and frozen elephant trunk for type A aortic dissection after Bentall procedure in Marfan syndrome.J Thorac Dis. 2018 Apr;10(4):2377-2387. doi: 10.21037/jtd.2018.03.79.
• [18] The stability of Magoh and Y14 depends on their heterodimer formation and nuclear localization.Biochem Biophys Res Commun. 2019 Apr 9;511(3):631-636. doi: 10.1016/j.bbrc.2019.02.097. Epub 2019 Feb 27.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [24] 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.
• [25] 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.
• [26] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [27] 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.
• [28] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [29] 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.
• [30] 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.
• [31] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [32] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [33] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [34] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.