Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHL77NY)

• DOT Name: U6 snRNA-associated Sm-like protein LSm2 (LSM2)
• Synonyms: Protein G7b; Small nuclear ribonuclear protein D homolog; snRNP core Sm-like protein Sm-x5
• Gene Name: LSM2
• Related Disease:
  Asthma
  Isolated congenital microcephaly
  Poliomyelitis
  Adult teratoma
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Herpes simplex infection
  Mixed connective tissue disease
  Non-small-cell lung cancer
  Parkinson disease
  Progressive myoclonus epilepsy
  Retinitis pigmentosa
  Riley-Day syndrome
  Spinal muscular atrophy
  Systemic lupus erythematosus
  Teratoma
  Unverricht-Lundborg syndrome
  Advanced cancer
  Amyotrophic lateral sclerosis
  Neurofibromatosis type 1
  Autoimmune disease
  Connective tissue disorder
  Motor neurone disease
  Retinitis pigmentosa 18
• UniProt ID: LSM2_HUMAN
• PDB ID: 3JCR; 5O9Z; 6AH0; 6AHD; 6QW6; 6QX9; 7ABG
• Pfam ID: PF01423
• Sequence:
  MLFYSFFKSLVGKDVVVELKNDLSICGTLHSVDQYLNIKLTDISVTDPEKYPHMLSVKNC
  FIRGSVVRYVQLPADEVDTQLLQDAARKEALQQKQ
• 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

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Definitive	Biomarker	[1]
Isolated congenital microcephaly	DISUXHZ6	Definitive	Biomarker	[2]
Poliomyelitis	DISANFJN	Definitive	Biomarker	[3]
Adult teratoma	DISBY81U	Strong	Genetic Variation	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[7]
Mixed connective tissue disease	DISXX0H8	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Parkinson disease	DISQVHKL	Strong	Biomarker	[5]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Biomarker	[10]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[11]
Riley-Day syndrome	DISJZHNP	Strong	Genetic Variation	[12]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[13]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[14]
Teratoma	DIS6ICY4	Strong	Genetic Variation	[4]
Unverricht-Lundborg syndrome	DISG4WLX	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[15]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[16]
Neurofibromatosis type 1	DIS53JH9	moderate	Biomarker	[17]
Autoimmune disease	DISORMTM	Disputed	Genetic Variation	[18]
Connective tissue disorder	DISKXBS3	Limited	Genetic Variation	[19]
Motor neurone disease	DISUHWUI	Limited	Biomarker	[16]
Retinitis pigmentosa 18	DIS9LWX6	Limited	Genetic Variation	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[26]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[28]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[29]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[31]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[32]
PP-242	DM2348V	Investigative	PP-242 increases the expression of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[33]

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 LSm2 (LSM2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of U6 snRNA-associated Sm-like protein LSm2 (LSM2).	[30]

References

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• [3] Inhibition of U snRNP assembly by a virus-encoded proteinase.Genes Dev. 2007 May 1;21(9):1086-97. doi: 10.1101/gad.1535607.
• [4] The complete primary structure of the human snRNP E protein.Nucleic Acids Res. 1988 Nov 25;16(22):10593-605. doi: 10.1093/nar/16.22.10593.
• [5] U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease.Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16562-7. doi: 10.1073/pnas.1310249110. Epub 2013 Sep 10.
• [6] HMGA1a Induces Alternative Splicing of the Estrogen Receptor-lpha Gene by Trapping U1 snRNP to an Upstream Pseudo-5' Splice Site.Front Mol Biosci. 2018 Jun 8;5:52. doi: 10.3389/fmolb.2018.00052. eCollection 2018.
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• [8] Mixed Connective Tissue Disease and Epitope Spreading: An Historical Cohort Study.J Clin Rheumatol. 2017 Apr;23(3):155-159. doi: 10.1097/RHU.0000000000000500.
• [9] Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer.Bioinformatics. 2016 May 1;32(9):1373-9. doi: 10.1093/bioinformatics/btw010. Epub 2016 Jan 10.
• [10] The gene for human U2 snRNP auxiliary factor small 35-kDa subunit (U2AF1) maps to the progressive myoclonus epilepsy (EPM1) critical region on chromosome 21q22.3.Genomics. 1996 Apr 15;33(2):298-300. doi: 10.1006/geno.1996.0196.
• [11] PRPF4 is a novel therapeutic target for the treatment of breast cancer by influencing growth, migration, invasion, and apoptosis of breast cancer cells via p38 MAPK signaling pathway.Mol Cell Probes. 2019 Oct;47:101440. doi: 10.1016/j.mcp.2019.101440. Epub 2019 Aug 22.
• [12] RBM24 promotes U1 snRNP recognition of the mutated 5' splice site in the IKBKAP gene of familial dysautonomia.RNA. 2017 Sep;23(9):1393-1403. doi: 10.1261/rna.059428.116. Epub 2017 Jun 7.
• [13] Negative cooperativity between Gemin2 and RNA provides insights into RNA selection and the SMN complex's release in snRNP assembly.Nucleic Acids Res. 2020 Jan 24;48(2):895-911. doi: 10.1093/nar/gkz1135.
• [14] Screening epitopes on systemic lupus erythematosus autoantigens with a peptide array.Oncotarget. 2017 Sep 18;8(49):85559-85567. doi: 10.18632/oncotarget.20994. eCollection 2017 Oct 17.
• [15] An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth.Genes Dev. 2014 May 15;28(10):1068-84. doi: 10.1101/gad.237206.113. Epub 2014 May 1.
• [16] U1 snRNP is mislocalized in ALS patient fibroblasts bearing NLS mutations in FUS and is required for motor neuron outgrowth in zebrafish.Nucleic Acids Res. 2015 Mar 31;43(6):3208-18. doi: 10.1093/nar/gkv157. Epub 2015 Mar 3.
• [17] Low U1 snRNP dependence at the NF1 exon 29 donor splice site.FEBS J. 2009 Apr;276(7):2060-73. doi: 10.1111/j.1742-4658.2009.06941.x.
• [18] Strict 3' splice site sequence requirements for U2 snRNP recruitment after U2AF binding underlie a genetic defect leading to autoimmune disease.RNA. 2011 Mar;17(3):401-11. doi: 10.1261/rna.2444811. Epub 2011 Jan 13.
• [19] T cell immunity in connective tissue disease patients targets the RNA binding domain of the U1-70kDa small nuclear ribonucleoprotein.J Immunol. 2002 Sep 15;169(6):3429-37. doi: 10.4049/jimmunol.169.6.3429.
• [20] Mutation in the splicing factor Hprp3p linked to retinitis pigmentosa impairs interactions within the U4/U6 snRNP complex.Hum Mol Genet. 2008 Jan 15;17(2):225-39. doi: 10.1093/hmg/ddm300. Epub 2007 Oct 11.
• [21] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [30] 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.
• [31] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [32] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [33] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.