Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTP9765)

• DOT Name: Male-specific lethal 3 homolog (MSL3)
• Synonyms: Male-specific lethal-3 homolog 1; Male-specific lethal-3 protein-like 1; MSL3-like 1
• Gene Name: MSL3
• Related Disease:
  Basilicata-Akhtar syndrome
  Intellectual disability
• UniProt ID: MS3L1_HUMAN
• PDB ID: 2Y0N; 3OA6; 3OB9
• Pfam ID: PF05712 ; PF11717
• Sequence:
  MSASEGMKFKFHSGEKVLCFEPDPTKARVLYDAKIVDVIVGKDEKGRKIPEYLIHFNGWN
  RSWDRWAAEDHVLRDTDENRRLQRKLARKAVARLRSTGRKKKRCRLPGVDSVLKGLPTEE
  KDENDENSLSSSSDCSENKDEEISEESDIEEKTEVKEEPELQTRREMEERTITIEIPEVL
  KKQLEDDCYYINRRKRLVKLPCQTNIITILESYVKHFAINAAFSANERPRHHHVMPHANM
  NVHYIPAEKNVDLCKEMVDGLRITFDYTLPLVLLYPYEQAQYKKVTSSKFFLPIKESATS
  TNRSQEELSPSPPLLNPSTPQSTESQPTTGEPATPKRRKAEPEALQSLRRSTRHSANCDR
  LSESSASPQPKRRQQDTSASMPKLFLHLEKKTPVHSRSSSPIPLTPSKEGSAVFAGFEGR
  RTNEINEVLSWKLVPDNYPPGDQPPPPSYIYGAQHLLRLFVKLPEILGKMSFSEKNLKAL
  LKHFDLFLRFLAEYHDDFFPESAYVAACEAHYSTKNPRAIY
• Function: Has a role in chromatin remodeling and transcriptional regulation. Has a role in X inactivation. Component of the MSL complex which is responsible for the majority of histone H4 acetylation at 'Lys-16' which is implicated in the formation of higher-order chromatin structure. Specifically recognizes histone H4 monomethylated at 'Lys-20' (H4K20Me1) in a DNA-dependent manner and is proposed to be involved in chromosomal targeting of the MSL complex.
• Tissue Specificity: Expressed in many tissues including liver, pancreas, heart, lung, kidney, skeletal muscle, brain, and placenta, with highest expression in skeletal muscle and heart.
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Basilicata-Akhtar syndrome	DISDWNF6	Definitive	X-linked	[1]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]

4 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 Male-specific lethal 3 homolog (MSL3).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Male-specific lethal 3 homolog (MSL3).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Male-specific lethal 3 homolog (MSL3).	[9]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Male-specific lethal 3 homolog (MSL3).	[11]

6 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 Male-specific lethal 3 homolog (MSL3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Male-specific lethal 3 homolog (MSL3).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Male-specific lethal 3 homolog (MSL3).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Male-specific lethal 3 homolog (MSL3).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Male-specific lethal 3 homolog (MSL3).	[7]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Male-specific lethal 3 homolog (MSL3).	[10]

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] De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation.Nat Genet. 2018 Oct;50(10):1442-1451. doi: 10.1038/s41588-018-0220-y. Epub 2018 Sep 17.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] 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.
• [9] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [10] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [11] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.