Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBXG37N)

• DOT Name: Elongator complex protein 2 (ELP2)
• Synonyms: ELP2; SHINC-2; STAT3-interacting protein 1; StIP1
• Gene Name: ELP2
• Related Disease:
  Cystic fibrosis
  Intellectual disability
  Intellectual disability, autosomal recessive 58
  Renal fibrosis
  Riley-Day syndrome
  Frontotemporal dementia
  Acute lymphocytic leukaemia
  Lymphoid leukemia
• UniProt ID: ELP2_HUMAN
• Pfam ID: PF00400
• Sequence:
  MVAPVLETSHVFCCPNRVRGVLNWSSGPRGLLAFGTSCSVVLYDPLKRVVVTNLNGHTAR
  VNCIQWICKQDGSPSTELVSGGSDNQVIHWEIEDNQLLKAVHLQGHEGPVYAVHAVYQRR
  TSDPALCTLIVSAAADSAVRLWSKKGPEVMCLQTLNFGNGFALALCLSFLPNTDVPILAC
  GNDDCRIHIFAQQNDQFQKVLSLCGHEDWIRGVEWAAFGRDLFLASCSQDCLIRIWKLYI
  KSTSLETQDDDNIRLKENTFTIENESVKIAFAVTLETVLAGHENWVNAVHWQPVFYKDGV
  LQQPVRLLSASMDKTMILWAPDEESGVWLEQVRVGEVGGNTLGFYDCQFNEDGSMIIAHA
  FHGALHLWKQNTVNPREWTPEIVISGHFDGVQDLVWDPEGEFIITVGTDQTTRLFAPWKR
  KDQSQVTWHEIARPQIHGYDLKCLAMINRFQFVSGADEKVLRVFSAPRNFVENFCAITGQ
  SLNHVLCNQDSDLPEGATVPALGLSNKAVFQGDIASQPSDEEELLTSTGFEYQQVAFQPS
  ILTEPPTEDHLLQNTLWPEVQKLYGHGYEIFCVTCNSSKTLLASACKAAKKEHAAIILWN
  TTSWKQVQNLVFHSLTVTQMAFSPNEKFLLAVSRDRTWSLWKKQDTISPEFEPVFSLFAF
  TNKITSVHSRIIWSCDWSPDSKYFFTGSRDKKVVVWGECDSTDDCIEHNIGPCSSVLDVG
  GAVTAVSVCPVLHPSQRYVVAVGLECGKICLYTWKKTDQVPEINDWTHCVETSQSQSHTL
  AIRKLCWKNCSGKTEQKEAEGAEWLHFASCGEDHTVKIHRVNKCAL
• Function: Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine). The elongator complex catalyzes the formation of carboxymethyluridine in the wobble base at position 34 in tRNAs.
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)
• BioCyc Pathway: MetaCyc:ENSG00000134759-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cystic fibrosis	DIS2OK1Q	Strong	Altered Expression	[1]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[2]
Intellectual disability, autosomal recessive 58	DIS0I8OE	Strong	Autosomal recessive	[3]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[4]
Riley-Day syndrome	DISJZHNP	Strong	Biomarker	[5]
Frontotemporal dementia	DISKYHXL	moderate	Genetic Variation	[6]
Acute lymphocytic leukaemia	DISPX75S	Limited	Biomarker	[7]
Lymphoid leukemia	DIS65TYQ	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Elongator complex protein 2 (ELP2).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Elongator complex protein 2 (ELP2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Elongator complex protein 2 (ELP2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Elongator complex protein 2 (ELP2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Elongator complex protein 2 (ELP2).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Elongator complex protein 2 (ELP2).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Elongator complex protein 2 (ELP2).	[14]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Elongator complex protein 2 (ELP2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Elongator complex protein 2 (ELP2).	[16]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Elongator complex protein 2 (ELP2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Elongator complex protein 2 (ELP2).	[17]

References

• [1] 4-Phenylbutyrate stimulates Hsp70 expression through the Elp2 component of elongator and STAT-3 in cystic fibrosis epithelial cells.J Biol Chem. 2011 Dec 30;286(52):45083-92. doi: 10.1074/jbc.M111.293282. Epub 2011 Nov 8.
• [2] ELP2 is a novel gene implicated in neurodevelopmental disabilities.Am J Med Genet A. 2015 Jun;167(6):1391-5. doi: 10.1002/ajmg.a.36935. Epub 2015 Apr 2.
• [3] Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.
• [4] Suppression of Elp2 prevents renal fibrosis and inflammation induced by unilateral ureter obstruction (UUO) via inactivating Stat3-regulated TGF-1 and NF-B pathways.Biochem Biophys Res Commun. 2018 Jun 22;501(2):400-407. doi: 10.1016/j.bbrc.2018.04.227.
• [5] The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system.Dis Model Mech. 2017 May 1;10(5):605-618. doi: 10.1242/dmm.028258. Epub 2017 Feb 6.
• [6] Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS.Sci Rep. 2017 Aug 21;7(1):8899. doi: 10.1038/s41598-017-09320-z.
• [7] STIP Regulates ERK1/2 Signaling Pathway Involved in Interaction with PP1 in Lymphoblastic Leukemia.Curr Mol Med. 2016;16(8):767-775. doi: 10.2174/1566524016666161018154401.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [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] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [16] 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.
• [17] 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.
• [18] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.