Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHMOGO1)

• DOT Name: U4/U6.U5 tri-snRNP-associated protein 1 (SART1)
• Synonyms: SNU66 homolog; hSnu66; Squamous cell carcinoma antigen recognized by T-cells 1; SART-1; hSART-1; U4/U6.U5 tri-snRNP-associated 110 kDa protein; allergen Hom s 1
• Gene Name: SART1
• Related Disease:
  Colorectal carcinoma
  Adult glioblastoma
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Fatty liver disease
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Neoplasm
  Non-alcoholic steatohepatitis
  Renal cell carcinoma
  Squamous cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Kidney cancer
  Renal carcinoma
• UniProt ID: SNUT1_HUMAN
• PDB ID: 4PYU; 5O9Z; 6AHD; 6QW6; 6QX9
• Pfam ID: PF19252 ; PF03343
• Sequence:
  MGSSKKHRGEKEAAGTTAAAGTGGATEQPPRHREHKKHKHRSGGSGGSGGERRKRSRERG
  GERGSGRRGAEAEARSSTHGRERSQAEPSERRVKREKRDDGYEAAASSKTSSGDASSLSI
  EETNKLRAKLGLKPLEVNAIKKEAGTKEEPVTADVINPMALRQREELREKLAAAKEKRLL
  NQKLGKIKTLGEDDPWLDDTAAWIERSRQLQKEKDLAEKRAKLLEEMDQEFGVSTLVEEE
  FGQRRQDLYSARDLQGLTVEHAIDSFREGETMILTLKDKGVLQEEEDVLVNVNLVDKERA
  EKNVELRKKKPDYLPYAEDESVDDLAQQKPRSILSKYDEELEGERPHSFRLEQGGTADGL
  RERELEEIRAKLRLQAQSLSTVGPRLASEYLTPEEMVTFKKTKRRVKKIRKKEKEVVVRA
  DDLLPLGDQTQDGDFGSRLRGRGRRRVSEVEEEKEPVPQPLPSDDTRVENMDISDEEEGG
  APPPGSPQVLEEDEAELELQKQLEKGRRLRQLQQLQQLRDSGEKVVEIVKKLESRQRGWE
  EDEDPERKGAIVFNATSEFCRTLGEIPTYGLAGNREEQEELMDFERDEERSANGGSESDG
  EENIGWSTVNLDEEKQQQDFSASSTTILDEEPIVNRGLAAALLLCQNKGLLETTVQKVAR
  VKAPNKSLPSAVYCIEDKMAIDDKYSRREEYRGFTQDFKEKDGYKPDVKIEYVDETGRKL
  TPKEAFRQLSHRFHGKGSGKMKTERRMKKLDEEALLKKMSSSDTPLGTVALLQEKQKAQK
  TPYIVLSGSGKSMNANTITK
• Function: Plays a role in mRNA splicing as a component of the U4/U6-U5 tri-snRNP, one of the building blocks of the spliceosome. May also bind to DNA.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Bladder cancer	DISUHNM0	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[3]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[5]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[7]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[4]
Kidney cancer	DISBIPKM	moderate	Altered Expression	[8]
Renal carcinoma	DISER9XT	moderate	Altered Expression	[8]

9 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 U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of U4/U6.U5 tri-snRNP-associated protein 1 (SART1).	[19]

References

• [1] A systems biology approach identifies SART1 as a novel determinant of both 5-fluorouracil and SN38 drug resistance in colorectal cancer.Mol Cancer Ther. 2012 Jan;11(1):119-31. doi: 10.1158/1535-7163.MCT-11-0510. Epub 2011 Oct 25.
• [2] Identification of novel SNPs in glioblastoma using targeted resequencing.PLoS One. 2011;6(6):e18158. doi: 10.1371/journal.pone.0018158. Epub 2011 Jun 10.
• [3] A new HIF-1/RANTES-driven pathway to hepatocellular carcinoma mediated by germline haploinsufficiency of SART1/HAF in mice.Hepatology. 2016 May;63(5):1576-91. doi: 10.1002/hep.28468. Epub 2016 Mar 7.
• [4] HAF drives the switch of HIF-1 to HIF-2 by activating the NF-B pathway, leading to malignant behavior of T24 bladder cancer cells.Int J Oncol. 2014 Feb;44(2):393-402. doi: 10.3892/ijo.2013.2210. Epub 2013 Dec 6.
• [5] HAF mediates the evasive resistance of anti-angiogenesis TKI through disrupting HIF-1 and HIF-2 balance in renal cell carcinoma.Oncotarget. 2017 Jul 25;8(30):49713-49724. doi: 10.18632/oncotarget.17923.
• [6] The two glycolytic markers GLUT1 and MCT1 correlate with tumor grade and survival in clear-cell renal cell carcinoma.PLoS One. 2018 Feb 26;13(2):e0193477. doi: 10.1371/journal.pone.0193477. eCollection 2018.
• [7] Identification of the autoantigen SART-1 as a candidate gene for the development of atopy.Hum Mol Genet. 2002 Sep 1;11(18):2143-6. doi: 10.1093/hmg/11.18.2143.
• [8] Hypoxia-Associated Factor (HAF) Mediates Neurofibromin Ubiquitination and Degradation Leading to Ras-ERK Pathway Activation in Hypoxia.Mol Cancer Res. 2019 May;17(5):1220-1232. doi: 10.1158/1541-7786.MCR-18-1080. Epub 2019 Jan 31.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] 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.
• [13] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [14] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [15] 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.
• [16] Benzo[a]pyrene increases the Nrf2 content by downregulating the Keap1 message. Toxicol Sci. 2010 Aug;116(2):549-61.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.