Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUVR2OO)

• DOT Name: Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2)
• Synonyms: Dynein 2 intermediate chain 2; WD repeat-containing protein 34
• Gene Name: DYNC2I2
• Related Disease:
  Short-rib thoracic dysplasia 11 with or without polydactyly
  Jeune syndrome
  Obsolete short rib-polydactyly syndrome, Verma-Naumoff type
• UniProt ID: DC2I2_HUMAN
• PDB ID: 6RLB; 6SC2
• Pfam ID: PF00400
• Sequence:
  MATRAQPGPLSQAGSAGVAALATVGVASGPGPGRPGPLQDETLGVASVPSQWRAVQGIRW
  ETKSCQTASIATASASAQARNHVDAQVQTEAPVPVSVQPPSQYDIPRLAAFLRRVEAMVI
  RELNKNWQSHAFDGFEVNWTEQQQMVSCLYTLGYPPAQAQGLHVTSISWNSTGSVVACAY
  GRLDHGDWSTLKSFVCAWNLDRRDLRPQQPSAVVEVPSAVLCLAFHPTQPSHVAGGLYSG
  EVLVWDLSRLEDPLLWRTGLTDDTHTDPVSQVVWLPEPGHSHRFQVLSVATDGKVLLWQG
  IGVGQLQLTEGFALVMQQLPRSTKLKKHPRGETEVGATAVAFSSFDPRLFILGTEGGFPL
  KCSLAAGEAALTRMPSSVPLRAPAQFTFSPHGGPIYSVSCSPFHRNLFLSAGTDGHVHLY
  SMLQAPPLTSLQLSLKYLFAVRWSPVRPLVFAAASGKGDVQLFDLQKSSQKPTVLIKQTQ
  DESPVYCLEFNSQQTQLLAAGDAQGTVKVWQLSTEFTEQGPREAEDLDCLAAEVAA
• Function: Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the intraflagellar transport (IFT) system. DYNC2I2 plays a major role in retrograde ciliary protein trafficking and in ciliogenesis. Required also to maintain a functional transition zone ; Acts as a negative regulator of the Toll-like and IL-1R receptor signaling pathways. Inhibits the MAP3K7-induced NF-kappa-B activation pathway. Inhibits MAP3K7 phosphorylation at 'Thr-184' and 'Thr-187' upon Il-1 beta stimulation.
• Tissue Specificity: Expressed in several cell lines (at protein level).
• Reactome Pathway: Intraflagellar transport (R-HSA-5620924)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Short-rib thoracic dysplasia 11 with or without polydactyly	DISFKLBY	Strong	Autosomal recessive	[1]
Jeune syndrome	DISLC357	Supportive	Autosomal recessive	[2]
Obsolete short rib-polydactyly syndrome, Verma-Naumoff type	DISS6UQH	Supportive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[17]

2 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 Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cytoplasmic dynein 2 intermediate chain 2 (DYNC2I2).	[13]

References

• [1] WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-B pathway in cilia. Am J Hum Genet. 2013 Nov 7;93(5):926-31. doi: 10.1016/j.ajhg.2013.10.007. Epub 2013 Oct 31.
• [2] Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy. Am J Hum Genet. 2013 Nov 7;93(5):932-44. doi: 10.1016/j.ajhg.2013.10.003. Epub 2013 Oct 31.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] 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.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [14] 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.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.