Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZHPV5M)

• DOT Name: DnaJ homolog subfamily B member 2 (DNAJB2)
• Synonyms: Heat shock 40 kDa protein 3; Heat shock protein J1; HSJ-1
• Gene Name: DNAJB2
• Related Disease:
  Charcot-Marie-Tooth disease axonal type 2T
  Amyotrophic lateral sclerosis
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 2
  Duchenne muscular dystrophy
  Hereditary motor and sensory neuropathy
  Huntington disease
  Kennedy disease
  Myopathy
  Neuronopathy, distal hereditary motor, autosomal recessive 5
  Spinal muscular atrophy
  Parkinsonian disorder
• UniProt ID: DNJB2_HUMAN
• PDB ID: 2LGW
• Pfam ID: PF00226
• Sequence:
  MASYYEILDVPRSASADDIKKAYRRKALQWHPDKNPDNKEFAEKKFKEVAEAYEVLSDKH
  KREIYDRYGREGLTGTGTGPSRAEAGSGGPGFTFTFRSPEEVFREFFGSGDPFAELFDDL
  GPFSELQNRGSRHSGPFFTFSSSFPGHSDFSSSSFSFSPGAGAFRSVSTSTTFVQGRRIT
  TRRIMENGQERVEVEEDGQLKSVTINGVPDDLALGLELSRREQQPSVTSRSGGTQVQQTP
  ASCPLDSDLSEDEDLQLAMAYSLSEMEAAGKKPAGGREAQHRRQGRPKAQHQDPGLGGTQ
  EGARGEATKRSPSPEEKASRCLIL
• Function: Functions as a co-chaperone, regulating the substrate binding and activating the ATPase activity of chaperones of the HSP70/heat shock protein 70 family. In parallel, also contributes to the ubiquitin-dependent proteasomal degradation of misfolded proteins. Thereby, may regulate the aggregation and promote the functional recovery of misfolded proteins like HTT, MC4R, PRKN, RHO and SOD1 and be crucial for many biological processes. Isoform 1 which is localized to the endoplasmic reticulum membranes may specifically function in ER-associated protein degradation of misfolded proteins.
• Tissue Specificity: More abundantly expressed in neocortex, cerebellum, spinal cord and retina where it is expressed by neuronal cells (at protein level) . Detected at much lower level in non-neuronal tissues including kidney, lung, heart, skeletal muscle, spleen and testis (at protein level) . Isoform 1 is more abundant in neocortex and cerebellum compared to isoform 2 (at protein level) .
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease axonal type 2T	DISJU9TL	Definitive	Autosomal recessive	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[2]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[2]
Charcot-Marie-Tooth disease type 2	DISR30O9	Strong	Genetic Variation	[3]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Altered Expression	[4]
Hereditary motor and sensory neuropathy	DISR0X2K	Strong	Genetic Variation	[3]
Huntington disease	DISQPLA4	Strong	Altered Expression	[5]
Kennedy disease	DISXZVM1	Strong	Altered Expression	[4]
Myopathy	DISOWG27	Strong	Altered Expression	[4]
Neuronopathy, distal hereditary motor, autosomal recessive 5	DIS3E3YO	Strong	Autosomal recessive	[6]
Spinal muscular atrophy	DISTLKOB	Strong	Genetic Variation	[7]
Parkinsonian disorder	DISHGY45	Limited	Genetic Variation	[7]

19 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 DnaJ homolog subfamily B member 2 (DNAJB2).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[17]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[18]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[19]
APR-246	DMNFADH	Phase 2	APR-246 increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[24]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[25]
L-Serine	DM6WPIS	Investigative	L-Serine increases the expression of DnaJ homolog subfamily B member 2 (DNAJB2).	[26]

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 DnaJ homolog subfamily B member 2 (DNAJB2).	[21]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Protein kinase CK2 modulates HSJ1 function through phosphorylation of the UIM2 domain.Hum Mol Genet. 2017 Feb 1;26(3):611-623. doi: 10.1093/hmg/ddw420.
• [3] HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum. Neurology. 2014 Nov 4;83(19):1726-32. doi: 10.1212/WNL.0000000000000966. Epub 2014 Oct 1.
• [4] DNAJB2 expression in normal and diseased human and mouse skeletal muscle.Am J Pathol. 2010 Jun;176(6):2901-10. doi: 10.2353/ajpath.2010.090663. Epub 2010 Apr 15.
• [5] Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase.J Clin Invest. 2006 May;116(5):1410-24. doi: 10.1172/JCI27607. Epub 2006 Apr 6.
• [6] A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation. Ann Neurol. 2012 Apr;71(4):509-19. doi: 10.1002/ana.22684.
• [7] Identification of a Large DNAJB2 Deletion in a Family with Spinal Muscular Atrophy and Parkinsonism.Hum Mutat. 2016 Nov;37(11):1180-1189. doi: 10.1002/humu.23055. Epub 2016 Aug 21.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] 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.
• [15] Darinaparsin induces a unique cellular response and is active in an arsenic trioxide-resistant myeloma cell line. Mol Cancer Ther. 2009 May;8(5):1197-206.
• [16] 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.
• [17] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [18] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [21] 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.
• [22] 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.
• [23] Redox-sensitive gene-regulatory events controlling aberrant matrix metalloproteinase-1 expression. Free Radic Biol Med. 2014 Sep;74:99-107. doi: 10.1016/j.freeradbiomed.2014.06.017. Epub 2014 Jun 25.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.
• [26] Mechanisms of L-Serine Neuroprotection in vitro Include ER Proteostasis Regulation. Neurotox Res. 2018 Jan;33(1):123-132. doi: 10.1007/s12640-017-9829-3. Epub 2017 Nov 2.