Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT97FS6C)

• DOT Name: Histone H3.2 (H3C13)
• Synonyms: H3-clustered histone 13; H3-clustered histone 14; H3-clustered histone 15; Histone H3/m; Histone H3/o
• Gene Name: H3C13
• Related Disease:
  Lupus
  Systemic lupus erythematosus
• UniProt ID: H32_HUMAN
• PDB ID: 2IIJ ; 2X4W ; 2X4X ; 2X4Y ; 3AV1 ; 3DB3 ; 3MO8 ; 3QO2 ; 3R93 ; 4MZF ; 4MZG ; 4MZH ; 4OUC ; 5B0Y ; 5B0Z ; 5B40 ; 5BO0 ; 5CIU ; 5VAC ; 6ACE ; 6FML ; 6T79 ; 6T7A ; 6T7B ; 6T7C ; 6T7D ; 6X59 ; 6X5A ; 6XJD ; 6Y5D ; 6Y5E ; 7BQZ ; 7BU9 ; 7JO9 ; 7JOA ; 7JZV ; 7PET ; 7PEU ; 7PEV ; 7PEW ; 7PEX ; 7PEY ; 7PEZ ; 7PF0 ; 7PF2 ; 7PF3 ; 7PF4 ; 7PF5 ; 7PF6 ; 7PFA ; 7PFC ; 7PFD ; 7PFE ; 7PFF ; 7PFT ; 7PFU ; 7PFV ; 7PFW ; 7PFX ; 7TAN ; 7U50 ; 7U51 ; 7U52 ; 7U53 ; 7UV9 ; 7UVA ; 7XCR ; 7XCT ; 7XD0 ; 7YRD ; 8AAG ; 8ATF ; 8AV6 ; 8JLB ; 8JLD
• Pfam ID: PF00125
• Sequence:
  MARTKQTARKSTGGKAPRKQLATKAARKSAPATGGVKKPHRYRPGTVALREIRRYQKSTE
  LLIRKLPFQRLVREIAQDFKTDLRFQSSAVMALQEASEAYLVGLFEDTNLCAIHAKRVTI
  MPKDIQLARRIRGERA
• Function: Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  Alcoholism (hsa05034)
  Shigellosis (hsa05131)
  Transcriptio.l misregulation in cancer (hsa05202)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)
  Formation of the beta-catenin (R-HSA-201722)
  PRC2 methylates histones and DNA (R-HSA-212300)
  Condensation of Prophase Chromosomes (R-HSA-2299718)
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  HDACs deacetylate histones (R-HSA-3214815)
  PKMTs methylate histone lysines (R-HSA-3214841)
  HDMs demethylate histones (R-HSA-3214842)
  HATs acetylate histones (R-HSA-3214847)
  RMTs methylate histone arginines (R-HSA-3214858)
  Chromatin modifying enzymes (R-HSA-3247509)
  SIRT1 negatively regulates rRNA expression (R-HSA-427359)
  ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression (R-HSA-427389)
  NoRC negatively regulates rRNA expression (R-HSA-427413)
  B-WICH complex positively regulates rRNA expression (R-HSA-5250924)
  DNA methylation (R-HSA-5334118)
  Transcriptional regulation by small RNAs (R-HSA-5578749)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 (R-HSA-5625886)
  Assembly of the ORC complex at the origin of replication (R-HSA-68616)
  RNA Polymerase I Promoter Opening (R-HSA-73728)
  RNA Polymerase I Promoter Escape (R-HSA-73772)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Meiotic recombination (R-HSA-912446)
  HCMV Early Events (R-HSA-9609690)
  HCMV Late Events (R-HSA-9610379)
  Transcriptional regulation of granulopoiesis (R-HSA-9616222)
  Defective pyroptosis (R-HSA-9710421)
  Amyloid fiber formation (R-HSA-977225)
  Chromatin modifications during the maternal to zygotic transition (MZT) (R-HSA-9821002)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Interleukin-7 signaling (R-HSA-1266695)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lupus	DISOKJWA	Strong	Biomarker	[1]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histone H3.2 (H3C13).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Histone H3.2 (H3C13).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Histone H3.2 (H3C13).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone H3.2 (H3C13).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone H3.2 (H3C13).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Histone H3.2 (H3C13).	[7]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Histone H3.2 (H3C13).	[8]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide increases the expression of Histone H3.2 (H3C13).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Histone H3.2 (H3C13).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone H3.2 (H3C13).	[10]
Bilirubin	DMI0V4O	Investigative	Bilirubin increases the expression of Histone H3.2 (H3C13).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Histone H3.2 (H3C13).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Histone H3.2 (H3C13).	[12]

References

• [1] Comprehensive Longitudinal Surveillance of the IgG Autoantibody Repertoire in Established Systemic Lupus Erythematosus.Arthritis Rheumatol. 2019 May;71(5):736-743. doi: 10.1002/art.40788. Epub 2019 Mar 24.
• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Influence of resveratrol on rheumatoid fibroblast-like synoviocytes analysed with gene chip transcription. Phytomedicine. 2013 Feb 15;20(3-4):310-8. doi: 10.1016/j.phymed.2012.09.020. Epub 2012 Nov 6.
• [8] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [9] Proteomic profile of aminoglutethimide-induced apoptosis in HL-60 cells: role of myeloperoxidase and arylamine free radicals. Chem Biol Interact. 2015 Sep 5;239:129-38.
• [10] Poly(ADP-ribose) glycohydrolase silencing-mediated H2B expression inhibits benzo(a)pyrene-induced carcinogenesis. Environ Toxicol. 2021 Mar;36(3):291-297. doi: 10.1002/tox.23034. Epub 2020 Oct 12.
• [11] 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.
• [12] 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.
• [13] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.