Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA45FTS)

• DOT Name: Transcription intermediary factor 1-alpha (TRIM24)
• Synonyms: TIF1-alpha; EC 2.3.2.27; E3 ubiquitin-protein ligase TRIM24; RING finger protein 82; RING-type E3 ubiquitin transferase TIF1-alpha; Tripartite motif-containing protein 24
• Gene Name: TRIM24
• UniProt ID: TIF1A_HUMAN
• PDB ID: 2YYN; 3O33; 3O34; 3O35; 3O36; 3O37; 4YAB; 4YAD; 4YAT; 4YAX; 4YBM; 4YBS; 4YBT; 4YC9; 4ZQL; 5H1T; 5H1U; 5H1V; 7B9X
• EC Number: 2.3.2.27
• Pfam ID: PF00439 ; PF00628 ; PF00643
• Sequence:
  MEVAVEKAVAAAAAASAAASGGPSAAPSGENEAESRQGPDSERGGEAARLNLLDTCAVCH
  QNIQSRAPKLLPCLHSFCQRCLPAPQRYLMLPAPMLGSAETPPPVPAPGSPVSGSSPFAT
  QVGVIRCPVCSQECAERHIIDNFFVKDTTEVPSSTVEKSNQVCTSCEDNAEANGFCVECV
  EWLCKTCIRAHQRVKFTKDHTVRQKEEVSPEAVGVTSQRPVFCPFHKKEQLKLYCETCDK
  LTCRDCQLLEHKEHRYQFIEEAFQNQKVIIDTLITKLMEKTKYIKFTGNQIQNRIIEVNQ
  NQKQVEQDIKVAIFTLMVEINKKGKALLHQLESLAKDHRMKLMQQQQEVAGLSKQLEHVM
  HFSKWAVSSGSSTALLYSKRLITYRLRHLLRARCDASPVTNNTIQFHCDPSFWAQNIINL
  GSLVIEDKESQPQMPKQNPVVEQNSQPPSGLSSNQLSKFPTQISLAQLRLQHMQQQVMAQ
  RQQVQRRPAPVGLPNPRMQGPIQQPSISHQQPPPRLINFQNHSPKPNGPVLPPHPQQLRY
  PPNQNIPRQAIKPNPLQMAFLAQQAIKQWQISSGQGTPSTTNSTSSTPSSPTITSAAGYD
  GKAFGSPMIDLSSPVGGSYNLPSLPDIDCSSTIMLDNIVRKDTNIDHGQPRPPSNRTVQS
  PNSSVPSPGLAGPVTMTSVHPPIRSPSASSVGSRGSSGSSSKPAGADSTHKVPVVMLEPI
  RIKQENSGPPENYDFPVVIVKQESDEESRPQNANYPRSILTSLLLNSSQSSTSEETVLRS
  DAPDSTGDQPGLHQDNSSNGKSEWLDPSQKSPLHVGETRKEDDPNEDWCAVCQNGGELLC
  CEKCPKVFHLSCHVPTLTNFPSGEWICTFCRDLSKPEVEYDCDAPSHNSEKKKTEGLVKL
  TPIDKRKCERLLLFLYCHEMSLAFQDPVPLTVPDYYKIIKNPMDLSTIKKRLQEDYSMYS
  KPEDFVADFRLIFQNCAEFNEPDSEVANAGIKLENYFEELLKNLYPEKRFPKPEFRNESE
  DNKFSDDSDDDFVQPRKKRLKSIEERQLLK
• Function: Transcriptional coactivator that interacts with numerous nuclear receptors and coactivators and modulates the transcription of target genes. Interacts with chromatin depending on histone H3 modifications, having the highest affinity for histone H3 that is both unmodified at 'Lys-4' (H3K4me0) and acetylated at 'Lys-23' (H3K23ac). Has E3 protein-ubiquitin ligase activity. During the DNA damage response, participates in an autoregulatory feedback loop with TP53. Early in response to DNA damage, ATM kinase phosphorylates TRIM24 leading to its ubiquitination and degradation. After sufficient DNA repair has occurred, TP53 activates TRIM24 transcription, ultimately leading to TRIM24-mediated TP53 ubiquitination and degradation. Plays a role in the regulation of cell proliferation and apoptosis, at least in part via its effects on p53/TP53 levels. Up-regulates ligand-dependent transcription activation by AR, GCR/NR3C1, thyroid hormone receptor (TR) and ESR1. Modulates transcription activation by retinoic acid (RA) receptors, including RARA. Plays a role in regulating retinoic acid-dependent proliferation of hepatocytes. Participates also in innate immunity by mediating the specific 'Lys-63'-linked ubiquitination of TRAF3 leading to activation of downstream signal transduction of the type I IFN pathway. Additionally, negatively regulates NLRP3/CASP1/IL-1beta-mediated pyroptosis and cell migration probably by ubiquitinating NLRP3.
• Reactome Pathway:
  Signaling by FGFR1 in disease (R-HSA-5655302)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Signaling by cytosolic FGFR1 fusion mutants (R-HSA-1839117)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Transcription intermediary factor 1-alpha (TRIM24) increases the response to substance of Arsenic trioxide.	[21]

18 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 Transcription intermediary factor 1-alpha (TRIM24).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcription intermediary factor 1-alpha (TRIM24).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[11]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[18]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[19]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Transcription intermediary factor 1-alpha (TRIM24).	[20]

4 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 Transcription intermediary factor 1-alpha (TRIM24).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Transcription intermediary factor 1-alpha (TRIM24).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Transcription intermediary factor 1-alpha (TRIM24).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Transcription intermediary factor 1-alpha (TRIM24).	[16]

References

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• [2] 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.
• [3] 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.
• [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] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] 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.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Gene expression profiling reveals novel regulation by bisphenol-A in estrogen receptor-alpha-positive human cells. Environ Res. 2006 Jan;100(1):86-92.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.
• [20] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [21] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.