Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAPF4PA)

• DOT Name: RNA polymerase-associated protein LEO1 (LEO1)
• Synonyms: Replicative senescence down-regulated leo1-like protein
• Gene Name: LEO1
• Related Disease:
  Acute myelogenous leukaemia
  Malaria
• UniProt ID: LEO1_HUMAN
• PDB ID: 4M6T; 6GMH; 6TED; 7OOP; 7OPC; 7OPD; 7UNC; 7UND
• Pfam ID: PF04004
• Sequence:
  MADMEDLFGSDADSEAERKDSDSGSDSDSDQENAASGSNASGSESDQDERGDSGQPSNKE
  LFGDDSEDEGASHHSGSDNHSERSDNRSEASERSDHEDNDPSDVDQHSGSEAPNDDEDEG
  HRSDGGSHHSEAEGSEKAHSDDEKWGREDKSDQSDDEKIQNSDDEERAQGSDEDKLQNSD
  DDEKMQNTDDEERPQLSDDERQQLSEEEKANSDDERPVASDNDDEKQNSDDEEQPQLSDE
  EKMQNSDDERPQASDEEHRHSDDEEEQDHKSESARGSDSEDEVLRMKRKNAIASDSEADS
  DTEVPKDNSGTMDLFGGADDISSGSDGEDKPPTPGQPVDENGLPQDQQEEEPIPETRIEV
  EIPKVNTDLGNDLYFVKLPNFLSVEPRPFDPQYYEDEFEDEEMLDEEGRTRLKLKVENTI
  RWRIRRDEEGNEIKESNARIVKWSDGSMSLHLGNEVFDVYKAPLQGDHNHLFIRQGTGLQ
  GQAVFKTKLTFRPHSTDSATHRKMTLSLADRCSKTQKIRILPMAGRDPECQRTEMIKKEE
  ERLRASIRRESQQRRMREKQHQRGLSASYLEPDRYDEEEEGEESISLAAIKNRYKGGIRE
  ERARIYSSDSDEGSEEDKAQRLLKAKKLTSDEEGEPSGKRKAEDDDKANKKHKKYVISDE
  EEEDDD
• Function: Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Involved in polyadenylation of mRNA precursors. Connects PAF1C to Wnt signaling.
• Tissue Specificity: Highly expressed in skeletal muscle and heart. Weakly expressed in placenta and liver.
• Reactome Pathway:
  Formation of the beta-catenin (R-HSA-201722)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Malaria	DISQ9Y50	Strong	Genetic Variation	[2]

10 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 RNA polymerase-associated protein LEO1 (LEO1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of RNA polymerase-associated protein LEO1 (LEO1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RNA polymerase-associated protein LEO1 (LEO1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of RNA polymerase-associated protein LEO1 (LEO1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of RNA polymerase-associated protein LEO1 (LEO1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of RNA polymerase-associated protein LEO1 (LEO1).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RNA polymerase-associated protein LEO1 (LEO1).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of RNA polymerase-associated protein LEO1 (LEO1).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of RNA polymerase-associated protein LEO1 (LEO1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of RNA polymerase-associated protein LEO1 (LEO1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of RNA polymerase-associated protein LEO1 (LEO1).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of RNA polymerase-associated protein LEO1 (LEO1).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of RNA polymerase-associated protein LEO1 (LEO1).	[11]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of RNA polymerase-associated protein LEO1 (LEO1).	[14]

References

• [1] LEO1 is regulated by PRL-3 and mediates its oncogenic properties in acute myelogenous leukemia.Cancer Res. 2014 Jun 1;74(11):3043-53. doi: 10.1158/0008-5472.CAN-13-2321. Epub 2014 Mar 31.
• [2] A marker of glutathione S-transferase-mediated resistance to insecticides is associated with higher Plasmodium infection in the African malaria vector Anopheles funestus.Sci Rep. 2019 Apr 8;9(1):5772. doi: 10.1038/s41598-019-42015-1.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [14] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.