Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLKJB3A)

• DOT Name: U6 snRNA-associated Sm-like protein LSm4 (LSM4)
• Synonyms: Glycine-rich protein; GRP
• Gene Name: LSM4
• Related Disease: Astrocytoma
• UniProt ID: LSM4_HUMAN
• PDB ID: 3JCR; 5O9Z; 6AH0; 6AHD; 6QW6; 6QX9; 7ABG
• Pfam ID: PF01423
• Sequence:
  MLPLSLLKTAQNHPMLVELKNGETYNGHLVSCDNWMNINLREVICTSRDGDKFWRMPECY
  IRGSTIKYLRIPDEIIDMVKEEVVAKGRGRGGLQQQKQQKGRGMGGAGRGVFGGRGRGGI
  PGTGRGQPEKKPGRQAGKQ
• Function: Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex). The heptameric LSM2-8 complex binds specifically to the 3'-terminal U-tract of U6 snRNA.
• KEGG Pathway:
  R. degradation (hsa03018)
  Spliceosome (hsa03040)
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA decay by 5' to 3' exoribonuclease (R-HSA-430039)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Astrocytoma	DISL3V18	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[17]

2 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 U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of U6 snRNA-associated Sm-like protein LSm4 (LSM4).	[14]

References

• [1] Markers of mRNA stabilization and degradation, and RNAi within astrocytoma GW bodies.J Neurosci Res. 2007 Dec;85(16):3619-31. doi: 10.1002/jnr.21439.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] 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.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] 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.
• [10] 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.
• [11] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [12] 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.
• [13] Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro. Oncotarget. 2014 Dec 30;5(24):12891-907.
• [14] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [15] 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.
• [16] 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.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.