Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPF5H2I)

• DOT Name: Dynein light chain Tctex-type 1 (DYNLT1)
• Synonyms: Protein CW-1; T-complex testis-specific protein 1 homolog
• Gene Name: DYNLT1
• Related Disease: Male infertility
• UniProt ID: DYLT1_HUMAN
• PDB ID: 5JPW; 8J07
• Pfam ID: PF03645
• Sequence:
  MEDYQAAEETAFVVDEVSNIVKEAIESAIGGNAYQHSKVNQWTTNVVEQTLSQLTKLGKP
  FKYIVTCVIMQKNGAGLHTASSCFWDSSTDGSCTVRWENKTMYCIVSAFGLSI
• Function: Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. Binds to transport cargos and is involved in apical cargo transport such as rhodopsin-bearing vesicles in polarized epithelia. May also be a accessory component of axonemal dynein.; Plays a role in neuronal morphogenesis; the function is independent of cytoplasmic dynein and seems to be coupled to regulation of the actin cytoskeleton by enhancing Rac1 activity. The function in neurogenesis may be regulated by association with a G-protein beta-gamma dimer. May function as a receptor-independent activator of heterotrimeric G-protein signaling; the activation appears to be independent of a nucleotide exchange. Plays a role in regulating neurogenesis; inhibits the genesis of neurons from precursor cells during cortical development presumably by antagonizing ARHGEF2. Involved in the regulation of mitotic spindle orientation. Unrelated to the role in retrograde microtubule-associated movement may play a role in the dimerization of cytoplasmic proteins/domains such as for ACVR2B. Binds to the cytoplasmic domain of ACVR2B and, in vitro, inhibits ACVR2B signaling ; (Microbial infection) Is involved in intracellular targeting of D-type retrovirus gag polyproteins to the cytoplasmic assembly site.
• Tissue Specificity: Expressed in heart, placenta, skeletal muscle kidney, pancreas, spleen, prostate, testis, ovary, ileum and colon. Expressed in lung endothelial and smooth muscle cells (at protein level).
• KEGG Pathway:
  Motor proteins (hsa04814)
  Salmonella infection (hsa05132)
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Male infertility	DISY3YZZ	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dynein light chain Tctex-type 1 (DYNLT1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dynein light chain Tctex-type 1 (DYNLT1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dynein light chain Tctex-type 1 (DYNLT1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dynein light chain Tctex-type 1 (DYNLT1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dynein light chain Tctex-type 1 (DYNLT1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dynein light chain Tctex-type 1 (DYNLT1).	[7]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Dynein light chain Tctex-type 1 (DYNLT1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dynein light chain Tctex-type 1 (DYNLT1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dynein light chain Tctex-type 1 (DYNLT1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Dynein light chain Tctex-type 1 (DYNLT1).	[9]

References

• [1] Relationship between DYNLT1 and Beclin1 expression and the fertilising potential of human spermatozoa.Andrologia. 2019 Nov;51(10):e13380. doi: 10.1111/and.13380. Epub 2019 Aug 5.
• [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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] 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.
• [8] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [9] 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.
• [10] 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.
• [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.