Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT02TSQT)

• DOT Name: U1 small nuclear ribonucleoprotein A (SNRPA)
• Synonyms: U1 snRNP A; U1-A; U1A
• Gene Name: SNRPA
• Related Disease:
  Intellectual disability
  Glomerulonephritis
  Hepatocellular carcinoma
  Lupus
  Nephritis
  Systemic lupus erythematosus
  Gastric cancer
  Neoplasm
  Stomach cancer
  Mixed connective tissue disease
  Complex neurodevelopmental disorder
• UniProt ID: SNRPA_HUMAN
• PDB ID: 1AUD ; 1DRZ ; 1DZ5 ; 1FHT ; 1M5K ; 1M5O ; 1M5P ; 1M5V ; 1NU4 ; 1OIA ; 1SJ3 ; 1SJ4 ; 1SJF ; 1U6B ; 1URN ; 1VBX ; 1VBY ; 1VBZ ; 1VC0 ; 1VC5 ; 1VC6 ; 1ZZN ; 2A3J ; 2NZ4 ; 2OIH ; 2OJ3 ; 2U1A ; 3BO2 ; 3BO3 ; 3BO4 ; 3CUL ; 3CUN ; 3EGZ ; 3G8S ; 3G8T ; 3G96 ; 3G9C ; 3HHN ; 3IIN ; 3IRW ; 3IWN ; 3K0J ; 3L3C ; 3MUM ; 3MUR ; 3MUT ; 3MUV ; 3MXH ; 3P49 ; 3PGW ; 3R1H ; 3R1L ; 3UCU ; 3UCZ ; 3UD3 ; 3UD4 ; 4C4W ; 4PR6 ; 4PRF ; 4W90 ; 4W92 ; 4YB1 ; 5DDO ; 5DDP ; 5DDQ ; 5DDR ; 5FJ4 ; 6LAS ; 6LAU ; 6LAX ; 6LAZ ; 6QX9 ; 6SQN ; 6SQQ ; 6SQT ; 6SQV ; 6SR7 ; 6XH0 ; 6XH1 ; 6XH2 ; 6XH3 ; 7AEP ; 7B0Y ; 7D7V ; 7DLZ ; 7DWH ; 7LHX ; 7QR3 ; 7QR4 ; 7VPX ; 8GXB ; 8GXC
• Pfam ID: PF00076
• Sequence:
  MAVPETRPNHTIYINNLNEKIKKDELKKSLYAIFSQFGQILDILVSRSLKMRGQAFVIFK
  EVSSATNALRSMQGFPFYDKPMRIQYAKTDSDIIAKMKGTFVERDRKREKRKPKSQETPA
  TKKAVQGGGATPVVGAVQGPVPGMPPMTQAPRIMHHMPGQPPYMPPPGMIPPPGLAPGQI
  PPGAMPPQQLMPGQMPPAQPLSENPPNHILFLTNLPEETNELMLSMLFNQFPGFKEVRLV
  PGRHDIAFVEFDNEVQAGAARDALQGFKITQNNAMKISFAKK
• Function: Component of the spliceosomal U1 snRNP, which is essential for recognition of the pre-mRNA 5' splice-site and the subsequent assembly of the spliceosome. U1 snRNP is the first snRNP to interact with pre-mRNA. This interaction is required for the subsequent binding of U2 snRNP and the U4/U6/U5 tri-snRNP. SNRPA binds stem loop II of U1 snRNA. In a snRNP-free form (SF-A) may be involved in coupled pre-mRNA splicing and polyadenylation process. May bind preferentially to the 5'-UGCAC-3' motif on RNAs.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Glomerulonephritis	DISPZIQ3	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Lupus	DISOKJWA	Strong	Biomarker	[4]
Nephritis	DISQZQ70	Strong	Biomarker	[4]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[5]
Neoplasm	DISZKGEW	moderate	Altered Expression	[5]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[5]
Mixed connective tissue disease	DISXX0H8	Disputed	Biomarker	[6]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal recessive	[7]

1 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 U1 small nuclear ribonucleoprotein A (SNRPA).	[8]

18 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 U1 small nuclear ribonucleoprotein A (SNRPA).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[15]
Marinol	DM70IK5	Approved	Marinol increases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[17]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[18]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of U1 small nuclear ribonucleoprotein A (SNRPA).	[26]

References

• [1] Exome sequencing reveals three homozygous missense variants in SNRPA in two sisters with syndromic intellectual disability.Clin Genet. 2018 Jun;93(6):1229-1233. doi: 10.1111/cge.13235. Epub 2018 Mar 9.
• [2] Altered expression level of a systemic nuclear autoantigen determines the fate of immune response to self.J Immunol. 1999 Jun 1;162(11):6482-91.
• [3] Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray.Oncol Rep. 2007 Oct;18(4):943-51.
• [4] Structural availability influences the capacity of autoantigenic epitopes to induce a widespread lupus-like autoimmune response.Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3551-6. doi: 10.1073/pnas.0306267101. Epub 2004 Feb 26.
• [5] SNRPA enhances tumour cell growth in gastric cancer through modulating NGF expression.Cell Prolif. 2018 Oct;51(5):e12484. doi: 10.1111/cpr.12484. Epub 2018 Jul 24.
• [6] Clonotype analysis of peripheral blood T cells and autoantigen-reactive T cells from patients with mixed connective tissue disease.J Immunol. 1994 Oct 15;153(8):3784-90.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] 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.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] 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.
• [12] Analysis of the in vitro synergistic effect of 5-fluorouracil and cisplatin on cervical carcinoma cells. Int J Gynecol Cancer. 2006 May-Jun;16(3):1321-9.
• [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] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [15] 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.
• [16] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [17] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [18] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [19] 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.
• [20] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [21] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [22] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [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] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [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.