Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY85YR4)

• DOT Name: KAT8 regulatory NSL complex subunit 2 (KANSL2)
• Synonyms: NSL complex protein NSL2; Non-specific lethal 2 homolog
• Gene Name: KANSL2
• UniProt ID: KANL2_HUMAN
• PDB ID: 4CY2
• Pfam ID: PF13891
• Sequence:
  MNRIRIHVLPTNRGRITPVPRSQEPLSCAFTHRPCSHPRLEGQEFCIKHILEDKNAPFKQ
  CSYISTKNGKRCPNAAPKPEKKDGVSFCAEHVRRNALALHAQMKKTNPGPVGETLLCQLS
  SYAKTELGSQTPESSRSEASRILDEDSWSDGEQEPITVDQTWRGDPDSEADSIDSDQEDP
  LKHAGVYTAEEVALIMREKLIRLQSLYIDQFKRLQHLLKEKKRRYLHNRKVEHEALGSSL
  LTGPEGLLAKERENLKRLKCLRRYRQRYGVEALLHRQLKERRMLATDGAAQQAHTTRSSQ
  RCLAFVDDVRCSNQSLPMTRHCLTHICQDTNQVLFKCCQGSEEVPCNKPVPVSLSEDPCC
  PLHFQLPPQMYKPEQVLSVPDDLEAGPMDLYLSAAELQPTESLPLEFSDDLDVVGDGMQC
  PPSPLLFDPSLTLEDHLVKEIAEDPVDILGQMQMAGDGCRSQGSRNSEKASAPLSQSGLA
  TANGKPEPTSIS
• Function: As part of the NSL complex it is involved in acetylation of nucleosomal histone H4 on several lysine residues and therefore may be involved in the regulation of transcription.
• Reactome Pathway:
  Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)
  HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of KAT8 regulatory NSL complex subunit 2 (KANSL2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of KAT8 regulatory NSL complex subunit 2 (KANSL2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of KAT8 regulatory NSL complex subunit 2 (KANSL2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of KAT8 regulatory NSL complex subunit 2 (KANSL2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of KAT8 regulatory NSL complex subunit 2 (KANSL2).	[5]
Selenium	DM25CGV	Approved	Selenium decreases the expression of KAT8 regulatory NSL complex subunit 2 (KANSL2).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of KAT8 regulatory NSL complex subunit 2 (KANSL2).	[9]

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 KAT8 regulatory NSL complex subunit 2 (KANSL2).	[6]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of KAT8 regulatory NSL complex subunit 2 (KANSL2).	[8]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [9] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.