Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7G4COD)

• DOT Name: RNA-binding protein with serine-rich domain 1 (RNPS1)
• Synonyms: SR-related protein LDC2
• Gene Name: RNPS1
• Related Disease:
  Malaria
  Advanced cancer
  Breast neoplasm
  Frontotemporal dementia
  Mood disorder
  Non-small-cell lung cancer
  Osteoglophonic dwarfism
  Pick disease
  Prostate cancer
  Prostate carcinoma
  Scleroderma
  Systemic sclerosis
  Acute myelogenous leukaemia
  Human papillomavirus infection
  Intellectual disability
  Lactic acidosis
• UniProt ID: RNPS1_HUMAN
• PDB ID: 4A8X
• Pfam ID: PF00076
• Sequence:
  MDLSGVKKKSLLGVKENNKKSSTRAPSPTKRKDRSDEKSKDRSKDKGATKESSEKDRGRD
  KTRKRRSASSGSSSTRSRSSSTSSSGSSTSTGSSSGSSSSSASSRSGSSSTSRSSSSSSS
  SGSPSPSRRRHDNRRRSRSKSKPPKRDEKERKRRSPSPKPTKVHIGRLTRNVTKDHIMEI
  FSTYGKIKMIDMPVERMHPHLSKGYAYVEFENPDEAEKALKHMDGGQIDGQEITATAVLA
  PWPRPPPRRFSPPRRMLPPPPMWRRSPPRMRRRSRSPRRRSPVRRRSRSPGRRRHRSRSS
  SNSSR
• Function: Part of pre- and post-splicing multiprotein mRNP complexes. Auxiliary component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction 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. Component of the ASAP and PSAP complexes which bind RNA in a sequence-independent manner and are proposed to be recruited to the EJC prior to or during the splicing process and to regulate specific excision of introns in specific transcription subsets. The ASAP complex can inhibit RNA processing during in vitro splicing reactions. The ASAP complex promotes apoptosis and is disassembled after induction of apoptosis. Enhances the formation of the ATP-dependent A complex of the spliceosome. Involved in both constitutive splicing and, in association with SRP54 and TRA2B/SFRS10, in distinctive modulation of alternative splicing in a substrate-dependent manner. 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 activity is different from the established EJC assembly and function. Participates in mRNA 3'-end cleavage. Involved in UPF2-dependent nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Also mediates increase of mRNA abundance and translational efficiency. Binds spliced mRNA 20-25 nt upstream of exon-exon junctions.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  mR. surveillance pathway (hsa03015)
• 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

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malaria	DISQ9Y50	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[4]
Mood disorder	DISLVMWO	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Osteoglophonic dwarfism	DISVSNPT	Strong	Altered Expression	[7]
Pick disease	DISP6X50	Strong	Genetic Variation	[4]
Prostate cancer	DISF190Y	Strong	Altered Expression	[8]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[8]
Scleroderma	DISVQ342	Strong	Biomarker	[9]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[9]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[10]
Human papillomavirus infection	DISX61LX	Limited	Altered Expression	[11]
Intellectual disability	DISMBNXP	Limited	Biomarker	[12]
Lactic acidosis	DISZI1ZK	Limited	Biomarker	[12]

5 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 RNA-binding protein with serine-rich domain 1 (RNPS1).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RNA-binding protein with serine-rich domain 1 (RNPS1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of RNA-binding protein with serine-rich domain 1 (RNPS1).	[23]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of RNA-binding protein with serine-rich domain 1 (RNPS1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of RNA-binding protein with serine-rich domain 1 (RNPS1).	[25]

10 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 RNA-binding protein with serine-rich domain 1 (RNPS1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RNA-binding protein with serine-rich domain 1 (RNPS1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of RNA-binding protein with serine-rich domain 1 (RNPS1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RNA-binding protein with serine-rich domain 1 (RNPS1).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA-binding protein with serine-rich domain 1 (RNPS1).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of RNA-binding protein with serine-rich domain 1 (RNPS1).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of RNA-binding protein with serine-rich domain 1 (RNPS1).	[21]
Selenium	DM25CGV	Approved	Selenium increases the expression of RNA-binding protein with serine-rich domain 1 (RNPS1).	[22]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of RNA-binding protein with serine-rich domain 1 (RNPS1).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of RNA-binding protein with serine-rich domain 1 (RNPS1).	[26]

References

• [1] Inhibition of the SR protein-phosphorylating CLK kinases of Plasmodium falciparum impairs blood stage replication and malaria transmission.PLoS One. 2014 Sep 4;9(9):e105732. doi: 10.1371/journal.pone.0105732. eCollection 2014.
• [2] Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC.Cell Rep. 2012 Feb 23;1(2):110-7. doi: 10.1016/j.celrep.2011.12.001.
• [3] SR protein expression and CD44 splicing pattern in human breast tumours.Breast Cancer Res Treat. 2003 May;79(1):75-82. doi: 10.1023/a:1023338718974.
• [4] SR protein 9G8 modulates splicing of tau exon 10 via its proximal downstream intron, a clustering region for frontotemporal dementia mutations.Mol Cell Neurosci. 2007 Jan;34(1):48-58. doi: 10.1016/j.mcn.2006.10.004. Epub 2006 Nov 29.
• [5] Increased expression of splicing factor SRp20 mRNA in bipolar disorder patients.J Affect Disord. 2008 Sep;110(1-2):62-9. doi: 10.1016/j.jad.2008.01.003. Epub 2008 Feb 20.
• [6] A new function of the splicing factor SRSF2 in the control of E2F1-mediated cell cycle progression in neuroendocrine lung tumors.Cell Cycle. 2013 Apr 15;12(8):1267-78. doi: 10.4161/cc.24363. Epub 2013 Mar 21.
• [7] RNPS1 inhibition aggravates ischemic brain injury and promotes neuronal death.Biochem Biophys Res Commun. 2020 Feb 26;523(1):39-45. doi: 10.1016/j.bbrc.2019.11.185. Epub 2019 Dec 9.
• [8] RNA splicing and splicing regulator changes in prostate cancer pathology.Hum Genet. 2017 Sep;136(9):1143-1154. doi: 10.1007/s00439-017-1792-9. Epub 2017 Apr 5.
• [9] Human autoimmune sera as molecular probes for the identification of an autoantigen kinase signaling pathway.J Exp Med. 2002 Nov 4;196(9):1213-25. doi: 10.1084/jem.20021167.
• [10] 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.
• [11] Human papillomavirus regulation of SR proteins.Biochem Soc Trans. 2010 Aug;38(4):1116-21. doi: 10.1042/BST0381116.
• [12] The SR protein SC35 is responsible for aberrant splicing of the E1alpha pyruvate dehydrogenase mRNA in a case of mental retardation with lactic acidosis.Mol Cell Biol. 2005 Apr;25(8):3286-94. doi: 10.1128/MCB.25.8.3286-3294.2005.
• [13] 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.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [26] 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.