Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1X5YGJ)

• DOT Name: Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1)
• Synonyms: Dynein 2 light intermediate chain
• Gene Name: DYNC2LI1
• Related Disease:
  Narcolepsy
  Short-rib thoracic dysplasia 15 with polydactyly
  Short rib-polydactyly syndrome
  Ellis-van Creveld syndrome
  Jeune syndrome
• UniProt ID: DC2L1_HUMAN
• PDB ID: 6RLB; 6SC2
• Pfam ID: PF05783
• Sequence:
  MPSETLWEIAKAEVEKRGINGSEGDGAEIAEKFVFFIGSKNGGKTTIILRCLDRDEPPKP
  TLALEYTYGRRAKGHNTPKDIAHFWELGGGTSLLDLISIPITGDTLRTFSLVLVLDLSKP
  NDLWPTMENLLQATKSHVDKVIMKLGKTNAKAVSEMRQKIWNNMPKDHPDHELIDPFPVP
  LVIIGSKYDVFQDFESEKRKVICKTLRFVAHYYGASLMFTSKSEALLLKIRGVINQLAFG
  IDKSKSICVDQNKPLFITAGLDSFGQIGSPPVPENDIGKLHAHSPMELWKKVYEKLFPPK
  SINTLKDIKDPARDPQYAENEVDEMRIQKDLELEQYKRSSSKSWKQIELDS
• 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, facilitating the assembly of these organelles. Involved in the regulation of ciliary length.
• Tissue Specificity: Expressed in bone, brain, kidney, and cartilage . Lower expression in heart, liver, lung, placenta and thymus .
• KEGG Pathway:
  Motor proteins (hsa04814)
  Vasopressin-regulated water reabsorption (hsa04962)
  Salmonella infection (hsa05132)
• Reactome Pathway: Intraflagellar transport (R-HSA-5620924)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[1]
Short-rib thoracic dysplasia 15 with polydactyly	DISM7IVM	Definitive	Autosomal recessive	[2]
Short rib-polydactyly syndrome	DISY2RES	Strong	Genetic Variation	[3]
Ellis-van Creveld syndrome	DISWSKIF	Supportive	Autosomal recessive	[2]
Jeune syndrome	DISLC357	Supportive	Autosomal recessive	[3]

3 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 Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[12]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytoplasmic dynein 2 light intermediate chain 1 (DYNC2LI1).	[14]

References

• [1] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [2] DYNC2LI1 mutations broaden the clinical spectrum of dynein-2 defects. Sci Rep. 2015 Jul 1;5:11649. doi: 10.1038/srep11649.
• [3] Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome. Nat Commun. 2015 Jun 16;6:7092. doi: 10.1038/ncomms8092.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [10] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [11] 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.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.