Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL2ZFTX)

• DOT Name: DnaJ homolog subfamily B member 12 (DNAJB12)
• Gene Name: DNAJB12
• Related Disease: Acquired immune deficiency syndrome
• UniProt ID: DJB12_HUMAN
• PDB ID: 2CTP
• Pfam ID: PF00226 ; PF09320
• Sequence:
  MESNKDEAERCISIALKAIQSNQPDRALRFLEKAQRLYPTPRVRALIESLNQKPQTAGDQ
  PPPTDTTHATHRKAGGTDAPSANGEAGGESTKGYTAEQVAAVKRVKQCKDYYEILGVSRG
  ASDEDLKKAYRRLALKFHPDKNHAPGATEAFKAIGTAYAVLSNPEKRKQYDQFGDDKSQA
  ARHGHGHGDFHRGFEADISPEDLFNMFFGGGFPSSNVHVYSNGRMRYTYQQRQDRRDNQG
  DGGLGVFVQLMPILILILVSALSQLMVSSPPYSLSPRPSVGHIHRRVTDHLGVVYYVGDT
  FSEEYTGSSLKTVERNVEDDYIANLRNNCWKEKQQKEGLLYRARYFGDTDMYHRAQKMGT
  PSCSRLSEVQASLHG
• Function: Acts as a co-chaperone with HSPA8/Hsc70; required to promote protein folding and trafficking, prevent aggregation of client proteins, and promote unfolded proteins to endoplasmic reticulum-associated degradation (ERAD) pathway. Acts by determining HSPA8/Hsc70's ATPase and polypeptide-binding activities. Can also act independently of HSPA8/Hsc70: together with DNAJB14, acts as a chaperone that promotes maturation of potassium channels KCND2 and KCNH2 by stabilizing nascent channel subunits and assembling them into tetramers. While stabilization of nascent channel proteins is dependent on HSPA8/Hsc70, the process of oligomerization of channel subunits is independent of HSPA8/Hsc70. When overexpressed, forms membranous structures together with DNAJB14 and HSPA8/Hsc70 within the nucleus; the role of these structures, named DJANGOs, is still unclear ; (Microbial infection) In case of infection by polyomavirus, involved in the virus endoplasmic reticulum membrane penetration and infection.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acquired immune deficiency syndrome	DISL5UOX	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of DnaJ homolog subfamily B member 12 (DNAJB12).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of DnaJ homolog subfamily B member 12 (DNAJB12).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DnaJ homolog subfamily B member 12 (DNAJB12).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of DnaJ homolog subfamily B member 12 (DNAJB12).	[3]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of DnaJ homolog subfamily B member 12 (DNAJB12).	[3]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of DnaJ homolog subfamily B member 12 (DNAJB12).	[4]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of DnaJ homolog subfamily B member 12 (DNAJB12).	[7]

References

• [1] Identification of Genes Whose Expression Profile Is Associated with Non-Progression towards AIDS Using eQTLs.PLoS One. 2015 Sep 14;10(9):e0136989. doi: 10.1371/journal.pone.0136989. eCollection 2015.
• [2] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [3] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [4] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [5] 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.
• [6] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [7] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.