Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT38A1MA)

• DOT Name: Circadian-associated transcriptional repressor (CIART)
• Synonyms: ChIP-derived repressor of network oscillator; Chrono; Computationally highlighted repressor of the network oscillator
• Gene Name: CIART
• UniProt ID: CIART_HUMAN
• Pfam ID: PF15673
• Sequence:
  MDSPSSVSSYSSYSLSSSFPTSPVNSDFGFPSDSEREDKGAHGPRPDTVGQRGGSRPSPG
  PIRCRHRSKVSGNQHTPSHPKQRGSASPMAGSGAKRSRDGELETSLNTQGCTTEGDLLFA
  QKCKELQGFIPPLTDLLNGLKMGRFERGLSSFQQSVAMDRIQRIVGVLQKPQMGERYLGT
  LLQVEGMLKTWFPQIAAQKSSLGGGKHQLTKHFPSHHSDSAASSPASPMEKMDQTQLGHL
  ALKPKQPWHLTQWPAMNLTWIHTTPICNPPLSSPGTISFSHGPLGTGTGIGVILFLQHGV
  QPFTHSAPTTPVPPTTASPVIPGEPMKLSGEGPRCYSLPVTLPSDWSYTLSPPSLPTLAR
  KMTIGHREQQRSHPPVAADAHLLNL
• Function: Transcriptional repressor which forms a negative regulatory component of the circadian clock and acts independently of the circadian transcriptional repressors: CRY1, CRY2 and BHLHE41. In a histone deacetylase-dependent manner represses the transcriptional activator activity of the CLOCK-BMAL1 heterodimer. Abrogates the interaction of BMAL1 with the transcriptional coactivator CREBBP and can repress the histone acetyl-transferase activity of the CLOCK-BMAL1 heterodimer, reducing histone acetylation of its target genes. Rhythmically binds the E-box elements (5'-CACGTG-3') on circadian gene promoters and its occupancy shows circadian oscillation antiphasic to BMAL1. Interacts with the glucocorticoid receptor (NR3C1) and contributes to the repressive function in the glucocorticoid response.

Molecular Interaction Atlas (MIA) of This DOT

1 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 Circadian-associated transcriptional repressor (CIART).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Circadian-associated transcriptional repressor (CIART).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Circadian-associated transcriptional repressor (CIART).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Circadian-associated transcriptional repressor (CIART).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Circadian-associated transcriptional repressor (CIART).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Circadian-associated transcriptional repressor (CIART).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Circadian-associated transcriptional repressor (CIART).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Circadian-associated transcriptional repressor (CIART).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Circadian-associated transcriptional repressor (CIART).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Circadian-associated transcriptional repressor (CIART).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Circadian-associated transcriptional repressor (CIART).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Circadian-associated transcriptional repressor (CIART).	[12]

References

• [1] 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.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [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] 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.
• [7] 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.
• [8] The MT1G Gene in LUHMES Neurons Is a Sensitive Biomarker of Neurotoxicity. Neurotox Res. 2020 Dec;38(4):967-978. doi: 10.1007/s12640-020-00272-3. Epub 2020 Sep 1.
• [9] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [10] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [11] 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.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.