Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG4I2A1)

• DOT Name: Ribosomal biogenesis protein LAS1L (LAS1L)
• Synonyms: Endoribonuclease LAS1L; EC 3.1.-.-; Protein LAS1 homolog
• Gene Name: LAS1L
• Related Disease:
  Acquired immune deficiency syndrome
  Autosomal recessive distal spinal muscular atrophy 1
  Lung neoplasm
  Wilson-Turner syndrome
  Spinal muscular atrophy with respiratory distress type 2
  Intellectual disability
  Intellectual disability, autosomal dominant 40
  Motor neurone disease
  X-linked syndromic intellectual disability
• UniProt ID: LAS1L_HUMAN
• PDB ID: 8FL2; 8FL3; 8FL4
• EC Number: 3.1.-.-
• Pfam ID: PF04031
• Sequence:
  MSWESGAGPGLGSQGMDLVWSAWYGKCVKGKGSLPLSAHGIVVAWLSRAEWDQVTVYLFC
  DDHKLQRYALNRITVWRSRSGNELPLAVASTADLIRCKLLDVTGGLGTDELRLLYGMALV
  RFVNLISERKTKFAKVPLKCLAQEVNIPDWIVDLRHELTHKKMPHINDCRRGCYFVLDWL
  QKTYWCRQLENSLRETWELEEFREGIEEEDQEEDKNIVVDDITEQKPEPQDDGKSTESDV
  KADGDSKGSEEVDSHCKKALSHKELYERARELLVSYEEEQFTVLEKFRYLPKAIKAWNNP
  SPRVECVLAELKGVTCENREAVLDAFLDDGFLVPTFEQLAALQIEYEDGQTEVQRGEGTD
  PKSHKNVDLNDVLVPKPFSQFWQPLLRGLHSQNFTQALLERMLSELPALGISGIRPTYIL
  RWTVELIVANTKTGRNARRFSAGQWEARRGWRLFNCSASLDWPRMVESCLGSPCWASPQL
  LRIIFKAMGQGLPDEEQEKLLRICSIYTQSGENSLVQEGSEASPIGKSPYTLDSLYWSVK
  PASSSFGSEAKAQQQEEQGSVNDVKEEEKEEKEVLPDQVEEEEENDDQEEEEEDEDDEDD
  EEEDRMEVGPFSTGQESPTAENARLLAQKRGALQGSAWQVSSEDVRWDTFPLGRMPGQTE
  DPAELMLENYDTMYLLDQPVLEQRLEPSTCKTDTLGLSCGVGSGNCSNSSSSNFEGLLWS
  QGQLHGLKTGLQLF
• Function: Required for the synthesis of the 60S ribosomal subunit and maturation of the 28S rRNA. Functions as a component of the Five Friends of Methylated CHTOP (5FMC) complex; the 5FMC complex is recruited to ZNF148 by methylated CHTOP, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes. Required for the efficient pre-rRNA processing at both ends of internal transcribed spacer 2 (ITS2).
• Reactome Pathway: Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acquired immune deficiency syndrome	DISL5UOX	Strong	Biomarker	[1]
Autosomal recessive distal spinal muscular atrophy 1	DISA9P1I	Strong	Genetic Variation	[2]
Lung neoplasm	DISVARNB	Strong	Biomarker	[3]
Wilson-Turner syndrome	DISL3YW9	Strong	X-linked	[2]
Spinal muscular atrophy with respiratory distress type 2	DIS0ER12	Supportive	Unknown	[2]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[4]
Intellectual disability, autosomal dominant 40	DISAI0IH	Limited	X-linked recessive	[5]
Motor neurone disease	DISUHWUI	Limited	Genetic Variation	[4]
X-linked syndromic intellectual disability	DISG1YOH	Limited	X-linked	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ribosomal biogenesis protein LAS1L (LAS1L).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ribosomal biogenesis protein LAS1L (LAS1L).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Ribosomal biogenesis protein LAS1L (LAS1L).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ribosomal biogenesis protein LAS1L (LAS1L).	[19]

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 Ribosomal biogenesis protein LAS1L (LAS1L).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ribosomal biogenesis protein LAS1L (LAS1L).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ribosomal biogenesis protein LAS1L (LAS1L).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Ribosomal biogenesis protein LAS1L (LAS1L).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ribosomal biogenesis protein LAS1L (LAS1L).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ribosomal biogenesis protein LAS1L (LAS1L).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ribosomal biogenesis protein LAS1L (LAS1L).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Ribosomal biogenesis protein LAS1L (LAS1L).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ribosomal biogenesis protein LAS1L (LAS1L).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ribosomal biogenesis protein LAS1L (LAS1L).	[20]

References

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• [2] Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis. Neurology. 2014 Apr 15;82(15):1322-30. doi: 10.1212/WNL.0000000000000305. Epub 2014 Mar 19.
• [3] Positional cloning of the major quantitative trait locus underlying lung tumor susceptibility in mice.Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12642-7. doi: 10.1073/pnas.2133947100.
• [4] Nol9 Is a Spatial Regulator for the Human ITS2 Pre-rRNA Endonuclease-Kinase Complex.J Mol Biol. 2019 Sep 6;431(19):3771-3786. doi: 10.1016/j.jmb.2019.07.007. Epub 2019 Jul 6.
• [5] X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry. 2016 Jan;21(1):133-48. doi: 10.1038/mp.2014.193. Epub 2015 Feb 3.
• [6] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] 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.
• [13] 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.
• [14] 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.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.
• [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 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.