Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU39CFZ)

• DOT Name: Histone H2B type 1-N (H2BC15)
• Synonyms: Histone H2B.d; H2B/d
• Gene Name: H2BC15
• Related Disease:
  Major depressive disorder
  Schizophrenia
  Type-1 diabetes
  Systemic lupus erythematosus
• UniProt ID: H2B1N_HUMAN
• Pfam ID: PF00125
• Sequence:
  MPEPSKSAPAPKKGSKKAVTKAQKKDGKKRKRSRKESYSVYVYKVLKQVHPDTGISSKAM
  GIMNSFVNDIFERIAGEASRLAHYNKRSTITSREIQTAVRLLLPGELAKHAVSEGTKAVT
  KYTSSK
• 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)
  Viral carcinogenesis (hsa05203)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Cleavage of the damaged pyrimidine (R-HSA-110329)
  Recognition and association of DNA glycosylase with site containing an affected purine (R-HSA-110330)
  Cleavage of the damaged purine (R-HSA-110331)
  Meiotic synapsis (R-HSA-1221632)
  Packaging Of Telomere Ends (R-HSA-171306)
  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)
  DNA Damage/Telomere Stress Induced Senescence (R-HSA-2559586)
  HDACs deacetylate histones (R-HSA-3214815)
  HATs acetylate histones (R-HSA-3214847)
  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)
  Ub-specific processing proteases (R-HSA-5689880)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Deposition of new CENPA-containing nucleosomes at the centromere (R-HSA-606279)
  Assembly of the ORC complex at the origin of replication (R-HSA-68616)
  G2/M DNA damage checkpoint (R-HSA-69473)
  RNA Polymerase I Promoter Opening (R-HSA-73728)
  RNA Polymerase I Promoter Escape (R-HSA-73772)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)
  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)
  Inhibition of DNA recombination at telomere (R-HSA-9670095)
  Defective pyroptosis (R-HSA-9710421)
  Amyloid fiber formation (R-HSA-977225)
  Chromatin modifications during the maternal to zygotic transition (MZT) (R-HSA-9821002)
  Replacement of protamines by nucleosomes in the male pronucleus (R-HSA-9821993)
  Recognition and association of DNA glycosylase with site containing an affected pyrimidine (R-HSA-110328)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[1]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[2]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[3]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Histone H2B type 1-N (H2BC15).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histone H2B type 1-N (H2BC15).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone H2B type 1-N (H2BC15).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Histone H2B type 1-N (H2BC15).	[8]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of Histone H2B type 1-N (H2BC15).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Histone H2B type 1-N (H2BC15).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Histone H2B type 1-N (H2BC15).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Histone H2B type 1-N (H2BC15).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Histone H2B type 1-N (H2BC15).	[13]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Histone H2B type 1-N (H2BC15).	[14]

References

• [1] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [2] Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
• [3] A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.Nature. 2007 Aug 2;448(7153):591-4. doi: 10.1038/nature06010. Epub 2007 Jul 15.
• [4] GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.Genes Immun. 2014 Sep;15(6):347-54. doi: 10.1038/gene.2014.23. Epub 2014 May 29.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] Extremely low copper concentrations affect gene expression profiles of human prostate epithelial cell lines. Chem Biol Interact. 2010 Oct 6;188(1):214-9.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
• [10] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [13] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [14] An in vitro strategy using multiple human induced pluripotent stem cell-derived models to assess the toxicity of chemicals: A case study on paraquat. Toxicol In Vitro. 2022 Jun;81:105333. doi: 10.1016/j.tiv.2022.105333. Epub 2022 Feb 16.