Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase MSL2 (MSL2)
• Synonyms: EC 2.3.2.-; E3 ubiquitin-protein transferase MSL2; Male-specific lethal 2-like 1; MSL2-like 1; Male-specific lethal-2 homolog; MSL-2; Male-specific lethal-2 homolog 1; RING finger protein 184
• Gene Name: MSL2
• Related Disease:
  Hepatocellular carcinoma
  Neoplasm
  Hepatitis B virus infection
  Coronary heart disease
  Myasthenia gravis
• UniProt ID: MSL2_HUMAN
• PDB ID: 4B7Y; 4B86
• EC Number: 2.3.2.-
• Pfam ID: PF16682 ; PF16685
• Sequence:
  MNPVNATALYISASRLVLNYDPGDPKAFTEINRLLPYFRQSLSCCVCGHLLQDPIAPTNS
  TCQHYVCKTCKGKKMMMKPSCSWCKDYEQFEENKQLSILVNCYKKLCEYITQTTLARDII
  EAVDCSSDILALLNDGSLFCEETEKPSDSSFTLCLTHSPLPSTSEPTTDPQASLSPMSES
  TLSIAIGSSVINGLPTYNGLSIDRFGINIPSPEHSNTIDVCNTVDIKTEDLSDSLPPVCD
  TVATDLCSTGIDICSFSEDIKPGDSLLLSVEEVLRSLETVSNTEVCCPNLQPNLEATVSN
  GPFLQLSSQSLSHNVFMSTSPALHGLSCTAATPKIAKLNRKRSRSESDSEKVQPLPISTI
  IRGPTLGASAPVTVKRESKISLQPIATVPNGGTTPKISKTVLLSTKSMKKSHEHGSKKSH
  SKTKPGILKKDKAVKEKIPSHHFMPGSPTKTVYKKPQEKKGCKCGRATQNPSVLTCRGQR
  CPCYSNRKACLDCICRGCQNSYMANGEKKLEAFAVPEKALEQTRLTLGINVTSIAVRNAS
  TSTSVINVTGSPVTTFLAASTHDDKSLDEAIDMRFDC
• Function: Component of histone acetyltransferase complex responsible for the majority of histone H4 acetylation at lysine 16 which is implicated in the formation of higher-order chromatin structure. Acts as an E3 ubiquitin ligase that promotes monoubiquitination of histone H2B at 'Lys-35' (H2BK34Ub), but not that of H2A. This activity is greatly enhanced by heterodimerization with MSL1. H2B ubiquitination in turn stimulates histone H3 methylation at 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) and leads to gene activation, including that of HOXA9 and MEIS1.
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[2]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[3]
Myasthenia gravis	DISELRCI	Limited	Altered Expression	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	E3 ubiquitin-protein ligase MSL2 (MSL2) increases the response to substance of Arsenic trioxide.	[16]

9 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 E3 ubiquitin-protein ligase MSL2 (MSL2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase MSL2 (MSL2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase MSL2 (MSL2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E3 ubiquitin-protein ligase MSL2 (MSL2).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of E3 ubiquitin-protein ligase MSL2 (MSL2).	[9]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of E3 ubiquitin-protein ligase MSL2 (MSL2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase MSL2 (MSL2).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E3 ubiquitin-protein ligase MSL2 (MSL2).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of E3 ubiquitin-protein ligase MSL2 (MSL2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of E3 ubiquitin-protein ligase MSL2 (MSL2).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase MSL2 (MSL2).	[13]

References

• [1] Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis.Oncol Lett. 2019 Nov;18(5):4984-4991. doi: 10.3892/ol.2019.10833. Epub 2019 Sep 10.
• [2] Hepatitis B virus X protein-elevated MSL2 modulates hepatitis B virus covalently closed circular DNA by inducing degradation of APOBEC3B to enhance hepatocarcinogenesis.Hepatology. 2017 Nov;66(5):1413-1429. doi: 10.1002/hep.29316. Epub 2017 Oct 11.
• [3] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [4] The long noncoding RNA MALAT-1 functions as a competing endogenous RNA to regulate MSL2 expression by sponging miR-338-3p in myasthenia gravis.J Cell Biochem. 2019 Apr;120(4):5542-5550. doi: 10.1002/jcb.27838. Epub 2018 Oct 26.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] 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.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.